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roteiп iпter ctiпg ith the So tic E ryogeпe i eceptor li e Kiп e 1 r j ll R ro otor r Dr r l r r m r ro otieco i ie r Dr A l r r Dr r l k r jm r Dr r l r Dr r r j ll R

roteiп iпter ctiпg ith the So tic E ryogeпe i eceptor li e Kiп e 1 r r r rkr j r r r r m r r Dr r lm r r m 2 j 2 m r r A l 8 8 8 8 Coпteпt 1. R l l r r k 2. A r r r r k m R 1 - r r 3. i i m m r R r-l k 1 r 14- - r 14 1 4. R 1 r r-l k k ll l r m l D 48 1 5. 14- - i i i r k 11 6. mm r 1 mm r 144 m 14 D k r 14 i i 1 1 Scope R r-l k r k R r r l m m l r R r r ll l r l r r ll r m r l k ll ll r ll r ll R r ll l r m r m m r m r ll l r l k m l R r m l r r ll l r m A l r m l m l R r l -r r RR r m m r r r RR r m r r r l l m r r r r l r k l r r - A m r l r l r l m r k r l r r r A r l k D- r r l r m r rr r l r - r r m r m l r l r m l i i m m r R r-l k 1 R 1 R l r l -r r l r m m r m l r - r k R r r l l m rl m r r R 1 r m m r rm l r R 1 r r r r l r l l m r l m r rk R 1 r i i l ll k - r A m j r l r r r l r r k m R 1 m l r m R 1 r r k l m l - r r R 1 k m r 1 r r l r l l k ll r r k r l r m r l r r m r l r r l 14- - r r 2 - r r r r r R 1 k m r l r r r r r ll r r r r r i i r r r r l i i R r l r R r 14- - r 14 R 1 r r R 1 14 r i i l ll rr R l r l l ll R 1 14 r i i - mm r ll r r l R r 4 l r R r AAA-A r D 48 R 1 r l D 48 r l R 1 r ll r r R 1 D 48 i i i i ll - mm r r l r r R 1 r r r l r r r r r 14- - m i i r k m l l l r m r r l r r r m l mm r Chapter Regulation of signal transduction via protein kinases Iпgrid M ieпtie, C per W roe eп пd S cco C de rie m r l r tr ct R r k r r m r r r ll l r r ll l r l r r k r l r m m m l l m l l r l r l A r l l r l l r r m r r r r k m r r r r r - m r r r k l r r r l r m r O r r l r 14- - r r r m r l r r r r k m m l l l r r k l l r l r r R l l r roteiп iп e r / r r k r l m l l r l r k r m l m i i m 2-4 ll r k A 2 1 r k l r r - A m k r r k r r r r / r r r r r r r m r l r r m l r l r A r r l k l l l l r r l - r l l m r ll rr r l m r l r ll l D r l l r A r l r - r r m r m l r l r r l -r rm l l r r r rr r l r - r r r l l m r k r r m 2 m r rr kD r l r r r l k rm k l r m l ll r m r / r r k l 1 8 Al l m r / r - r - k r r m l r l r m k r k m m r l 1 l 1 m ll r - rm l l m - r - 1- - l ll l l r r - rm l l r m l l l A l l l l r l r 1 2 - l -l l -r m m r r r A A r ll l l l r r - l rm r r r 2 2 r l r A- l l - A r Figure 1 m r m l r l k k r m l 1 8 ll r l r k l - l r l ll r m r - r r l ll egul tioп o proteiп iп e ctivity through pho phoryl tioп All k r rm m m l r r r r r rm r l r r m l r r r rm l r r r r l r m m l r k r k r l r l m k l r r r m r l r r l l k r m l 1 4 D r r r r l l m r r r r A k m r m l m r r l r l r r R l l r r 2 2 m k l r l k D r l l r l r rm l k l - r l m l k r r r m l l l r r k R l k r r A r l 1 ll l 2 1 r l l m r r r l r r l k l - rm l r l m m m r m r r l 1 r l l r l DA r k r l r r m r l r l m ll lm l r r m r r l m l r l r k r r rm l m m - r l 2 1 j m m r m r r k l l rm r m ll l k m r l k l r m rm r l r j m m r r r l r j m m r m k m l l r r r r r r m m r k r l 2 m l r m r - rm l k m r 1 r r - rm l l r l -r r k k r r r k r r 2 m ll r l r 2 r l m l k r m r m k m r r l r k r l m ll - rm l l k m r rm l r r l r k l A r 2 m r r m l r r r - r l r l - r r l m r r l k r r m r r A r l k l ll r l r l ll r k egul tioп o proteiп iп e ctivity through depho phoryl tioп r l r r l r r r k r r l m m m r r r l r m j r m l : r r/ r r r l r m l r l r r m r l r r r k r r r r ll l r m r r r r r/ r r m l l r r r l m m D l i i m 112 rk l 2 2 r m l r/ r m j r r 2 l 2 r r r r r r k - r A m l r l r m i r m l l r l r i i r A m l r r r-l k k ll l r l A AA ll r l 1 l r l R 1 r r k l 2 r l k r l r r l r l r ll r r - ll l r l l rr r r r r l ll ll l r j l l 2 2 l r - rm l m r l l m l m r r l r R r 1 8 - rm l m A m - rm l l r k r m m r A r l k l 1 8 l 2 2 r m l r l m l r l R l l r m l r l r k r r r r r l r ll l r l l m k r r l r r l r l A AA1 1 k m r r l l A r l rm 1 l r l 1 r r l ll m l 1 A r r l r 1 A m m l 1 r r k 1 R 1 l l r l A A r r l r l R l 2 2 r r k ll m m r k l l Loc li tioп пd odul tioп o proteiп iп e ctivity O r r k r l r m l r l r r l 2 2 l m mm l r 1 r r r l r ll r m r r l l r l l m m m r r rl m l m m r r r l r l k m r r l r - r r l r r - r r rm l r l rm r r r r r m m r r m r ll r r k r r - r r r r l r r r r l l k l 2 m m l l l r r r r r m r r ll m l rm r r m r ll r r r r r m m r m r l l r r l r r r r r r r r m m r l r r k r l m m l r r mm l r r m m r r r k r r l r r r r k r - r r m r m r m r r r l r r k r r r l r m r r r k A r r m r l ll l r l l k r k ll l r ll r l ll l r l l k l l m m m ll m r l Me r пe loc li tioп u iпg lipid пchor r l ll l r m r r r r m l l l r r l m m m r ll r ll l r m r m l k l m l k lm l r r r l r r r l r l r r r l ll l r l l ll r r l r l r r ll r rm m r r m r l r r l l l r r l l m m m r l m m r r r l 1 l r l lr r m m r l mm m m -m r l r l r l r r l m m r l r r r m r l m l l m m r r r l r r r r r l r l r l m m r r m l m l m m r m mm l -r r k r m r l l m m m r R l 1 4 r l r r r l m r r r r r r k l r r r l m r l r r m m m r A l r r m r r m m r r l R l l r roteiп proteiп iпter ctioп edi ted y proteiп iпdiпg do iп A r m r m m l l r r r m m r l r r k r r r - r r r r m l 2 2 k r r l k ll r r l k m r r r r l rm k - r m l m l l r r l r r r r r r ll l r r r l r r k r k 2 r m r r r r r r m l r r - r r A r m l r m r / r - m l l A D m l 2 14- - r r l r / r - m r m l k A D r ll r ll r 14- - r r m l l r r r l rk - A m m l r m 1 - m D r r l 2 2 A m m r r r r r m r k r r k r A m r r l r r r ll r D r A m r m rm m l k r l r r i i r A r r-l k k R R 1 A m r k r m l 1 l 2 2 r r A m A r r l r m r m R r l -1 -1 4 -1 - r 1 l r r 1 l 1 k m l l r r l m r l l l A: A m r m r l R l r l r rl m l r m r m ll r - r r m l 8-4 m l l 2 m r r r r r r 2 -22 m r l m r r l r r m m r r l -r m r r l r r r r m r r r r r-r r r-r r - r r r/ r m m l- r l l m r l - r m r r/ r- r l l 2 2 l r m r r r r r D A r l k m r r r r r r i i 1 r l k - m ll r-r r r-r r l l m r m 1 r l 2 2 l 1 - m r r l 14 i i r m l m R A l l r r l r A r A 4 1 r r AR l l 2 2 m l r m D r l -r r RR m m r m l r/ r m l - r l 2 1 r A m r r l r r r D r r RR m r- l k - r r r k 1- / ll - - l m l r m r r l r m r A r l 2 i i m r - r r m m D r RR m A 2 r - r D m m r r r m l r r m r r D r 44- r ll D - rm m l 1 A D r m m r 4 1 D r - r ll r l D r r l r r r rl r r l r m RR m r r m rr 2 -2 r l r r mm l l R l l r r - r r r r m l l D r 1 4 l m RR m r ll l r r r r l k k R r mm l r r m m r l 1 8 r m l i i 1 r r m ll r l m r m m r l 1 r r R 1 r r l r r l r l m l 2 d ptor, c old пd пchoriпg proteiп A m r rm k - r m l m l l r l r r r r k 2 r m m l m r - r r r l r r r m r / r rm l l r l r r A r r r ll l r r r l k l m m m r r l l m l r 1 l l m : r m r r l r r ll l r r r A r r r l k r m l r ll r 1 O r r r r r r m r l m l l r r m ll r r r r - r r l r r m m l l r r m l l r r r l r -l l r m l l r m ll r r ll r k 2 l l r r l r l r r r r ll l m ll l l r A m l l r l rm m - r k A m l l 2 A r m m r l r m l r r r k r r ll k r r l 2 k r A r k l m r r l r l r m r r r r r l r r r r ll l r r D r rm A l l 2 1 A m j r r r A k l m m m r r m r r l r l r l l l r l l m m m r l r - lk rm ll r r r r l l r r l A m l l A m r r l l l A l r l l m m m r r m l l l r m r r r l 2 1 l r r l r r - lk 14- - r r r l m l l m r r r r r r r r r ll r r m R r r m r r r l l 1 l 1 k l 2 2 r m 14- - r r l r m m m r r r r l 14- - r r m 14- - m mm l r r m l r l r m r r - m l DA- ll l r m r r l l r r r r 1 14- - r r m l m R l 2 m r l i i r l rm r m r l 1 r l r r rm r m 14- - r l 1 l 1 m l l 14- - m r r ll l - l r r l - r r 2 - rm l m rm m r r l r l - rm l m rm l r l r r r - l l R l l r m r rm r l r l r r rm r r l r r r r r r r m m r r l mm r r l r m r r l 1 14- - m r l r r r l Figure m r m l m mm l 14- - m m r k r m l 1 m l l 14- - m r r ll l - l r r l - r r - rm l m 14- - r rm m r r l r l - rm l m rm l Al 14- - rm r r m l r r l l r l r r r r r r r r l m r r r l r r i i 14- - rm r r r r m r - rm l l m m m r -A R l 2 14- - r r l l r r r jl l r 2 r r r l r l l 14- - r D r 14- - rm r r r r l m l / r r ll r r k l 1 m 14- - rm r l l ll l r m r m r m l i i 14 rm l l m m m r r 14 rm l m l r l r m k l 2 14- - r r m r m m r r r 14- - m r r r l r r r r r r m m l ll m l m r r r R -1 r k r l 2 r 14- - m r l l r r ll m m l R -1 r l r l 14- - ll k r 14- - r l ll 14- - r l l m l 14- - r rm r r r l r R -1 m 14- - m r l R -1 l r l r r r2 r 21 l 2 2 A R -1 k m r r l m 14- - r r m r2 R l R -1 l m m m r ll r l 14- - R - m r r r m - rm l m R 14- - R -1 r r m l m m m r r R -1 r ll ll R -r l m ll r l 2 2 14- - r m l m r r r/ l r 14- - r r l l r l r r r l r r l m r r r l l l l m r r l r r rm r r r r r r l ll Q m r 2 1 r R l l r l l l r l r l r m k m m D- rm r r r l r r l l l l l r r 14- - r l r r l l r l r rm1 r l 2 2 r r r r r r l r l r 14- - l r 14- - r - r l 1 14- - r m l r l l r l r r r r m r 14- - r r l r r r l l m k r l r l l r m r r r r l r - r ll - m l k 2 14- - r r r r ll l k 2 rm r r - - r m r l 2 1 D r r r D A m 2 r r r l 1 / k1 k l r 2 r r l 2 r l 2 l r m A r D A m 2 r r r r l k r k k1 r r r 14- - r A 14- - 2 r l r r m l r m r 2 ll l l k 14- - r k 2 l Al m 14- - r r r m l l l l m l r m r r r r r l l l r l 2 2 - r l 2 r 14- - r l r l r r 2 r 14- - - m r r 2 rm1 m l l l l r r 14- - r l 1 l l r l r l r R r l 1 r m r r l - l r r r r r r l 2 14- - m 4 l l r r -l k r m l l r r -l k l r 14- - r m l - l m r r m rk r r r R 1 R 1 r 14- - r l r l 2 2 r r r r m r r 14- - - r r m l l 14- - m l r m D 1 r r r l r m l l 14- - r r r 2 l R 1 14- - r m l l l r l r l ll l r l l 14- - r m l r l l m r l r r - m r r m k l r l l l D l l l m D 1 r l 2 2 14- - r m m l l r r r 14- - - m l rm r r r r r r r r r r 14- - r r l 2 2 l m r rm 14- - r -m l r k l r- l m r r Al l r 14- - r r r l r 14- - r ll r m l r 14- - r r r l r 14- - r r m r Kiп e igп l tteпu tioп пd receptor eпdocyto i D r l r r l m r l k m l r l r rl l r r m r rm l ll l r k r m l l r r l m m r l m r k A m r rm l r r r rr r l rm l r r r 2 2 r r r r r r r r-m R l l r l r r r r r l r r r r l r r r k r l m m m r r r r l r r r r l k 1 r r l l m l r m l r A l l r l l r r m r r ll r A r r l r r r r l r r r r m l m r m Al m r m r m r r r r m r r ll l r l 1 Am r r m l m r m r l k l m m m r l r r l m l r l r r l l r r k R l rk 2 1 A r l - l R r m l r m l D l r m R ll r r r l r l r m l rm l l r r k l m r l r r ll ll r l r r r r l m m r ll r l r r l 2 r m l m l rm l r r r r k r m l ll r l r r r r m m l rk 2 1 r r ll rm r l r ll m r ll l r r r l r l m m r r r r r k m - rm l m r r r r l r m r r l m r r l k ll r r l r r r m l r l m r r ll r r m m m l r l l ll r r r r r ll l r l r r m ll m l l r r r r r l r r l ll l r l r l 2 1 ll l r r r r m r l r r m r r l D1 r l m r r r l r r r l Coпclu ioп ll l rk r l r l r l l r l r r r m r l r k l r l m r l r l r l r r k m r r - r m r r r r A r l r m l r r l r l rm r m l r r ll r r r - lk l R l r l l l r r mm l m m r l l l - r r r r m l ll l r l l r m r l l ll l r l l r r ll r l r r lm ll m m r ll rk l m l m l l l l m l l m l r r ll m l ll- ll l r l l m ll l r l r l l m k k ll r r l ll l r r r r r r r r r R l l r e ereпce Х пdr de, M, oпz lez uz п, M, Serr пo, пd odrguez, L A m - m k l r l r i i m l - r i 1 Х eпo e Iпiti tive A l m l r l i i i Х Bev п,, Dr e,, Bergeroп, M пd o пer, B I r ll l r l r : r l m 1 1 Х Bh tп g r, S пd ordoп, I r l m r l : r ll l m l i 1 Х B gre, L, Me ieпe, I, He erle Bor E пd Hirt, H r r l A k m m l i Х Bruпet,, K п i, F, Stehп,, Xu,, S r ov, D, Fr пgioпi,, D l l, S N, DeC prio,, reeп erg, M E пd Y e, M B 14- - r l r m l l m r r i 1 Х Bur c, W пd Sh, S l r : l i i 1 11 Х D l l, S N, Sch eitzer, C M, п, пd DeC prio, l m l l m 2 r r r r 14- - i Х Deпu, M, Stuc ey,, S per, M пd Di oп, E rm r r l 1 Х Durocher, D пd c oп, S A m Х Elioп, E l i 11 Х Eпyedi,, er, K, Filoteo, пd eппi toп, T r k l m m m r m rm 4 r l r r r m lm l - m i 1 1 Х H п, S K пd Huпter, T k r r k r m l : k l m r r l Х v п He ert, M, Steeп, H Y пd v п Heu deп, H 14- - r : k r l r ll ll i Х Hic e, L : r ll- r r r r r r l i 1 11 r Х v п der Hoeveп, C, v п der W l, C M, uur,, v п Di, M C M пd v п Blitter i, W 14- - l l r k - R -1:

r l 14- - r l i Х Hu rd, S r l r r l r r r k m l r A l 1 1 Х Hu rd, S r : l i 11 Х Hu e, M пd Kuriy п, rm l l r k Х Iпterп tioп l Hu п eпo e Sequeпciпg Coп ortiu l l m m 1 Х ohп oп, L N, Lo e, E D, No le, E M пd O eп, D r r l r r r r l r k 1 11 Х Ke p, B E, r er, M W, Hu, S, Tig пi, T пd Hou e, C r r r r k : rm i i 1 Х Ker, D, Bulgrieп,, S ith, D W, B r п, B, eretпi, S пd ri ov, M m l m r l m i i i Х Kholodeп o, N, Hoe, B пd We terho, H l m ll r l r r ll m m r i 1 1 Х Ko e, B пd Die eпho er, l -r r : r l m i i 1 1 1 Х Ku g i, пd Duпphy, W 14- - r l r r r l r ll l r l l m r 2 1 1 1 Х L пdrieu, I Weiru ze i, M, Wiпt eп,, Iпze, D пd Lippeп, l r r l - m r l l / r m r 1A r m i i i Х Leo, E B r r r r ll : l l l i Х Letuпic, I, ood t dt, L, Dic eп, N, Doer, T, Schultz,, Mott,, Cicc relli, F, Copley,, oпtiпg, C пd Bor, R m r m AR m r r i i R l l r Х Li,, S ith, пd W l er, C r m k - r r - m i Х Light, Y, ter oп, H пd M r i, 14- - R -m R -1 r r m l m m m r m ll l i Х Liп, S Y, M iпo, K, Xi, W, M tiп,, Weп, Y, K oпg, K Y, Bourguigпoп, L пd Huпg, M C l r l l r r l r l r r r i Х Liu, D, Bieп o,, eto, C, Collier,, H l п, F пd Liddiпgtoп, r l r r rm 14- - r 1 1 1 Х Lopez iroп,, Furп ri, B, Moпde ert, O пd u ell, l r l l 2 r l D A m 14- - r 1 1 Х Lu,, hou, X, Liou, Y C Noel, пd Lu, K r l r l m r l r l r 1 i Х Moore, B W пd erez, r r m i i i i i i i i i Х Mu liп,, T ппer, W, lleп, M пd Sh, S r 14- - ll r m r r Х Mu liп, пd Xiпg, H 14- - r : r l ll l r l l m l l r r r i Х oп, T, iп, M пd N h, r m : r m m l m l ll l r r 1 Х oп, T пd Scott, D ll r l r r r i Х u ol,, B iп, T I, C yor,, Cort dell, N, Ferrer пd rio, i i i /4 : m l l r l r r l r mm l l r l i Х ui y, B B пd Cor ett, H l r r r m m i i 1 1 Х ittiпger, K, Bud п,, Xu,, oliпi, S, C пtley, L C, S erdoп, S, liп S пd Y e, M B r r l l 14- - m l l r l r l r r l 14- - l 1 1 r Х e h, M D r l lm l r m l m m r : m r 11 1 Х odriguez, L r 2 2 r l i 1 Х o eпqui t, M, Sehп e,, Ferl,, So riп, M пd L r oп, C l 14- - r m l : l r m r rm m l ll l r r m r l l Х Sehп e, C, DeLille, M пd Ferl, mm l r : r l 14- - r m l l- r r Х Sh h, K, u iпov, E, dell r, T W, Wille e, пd de rie, S C i i k - r r l r l m m r r r k 1 1 1 Х S ith, T F, it tze, C, S eп, K пd Neer, E D r : mm r r r r i i 1 1 1 Х Stoпe, M, Trotoch ud, E, W l er, C пd Cl r, S E r l m r m l m A AA1 r r k k - r r i 11 1 1 1 Х Strou, пd eпt, D m r l r r rm r r 1 Х Sudol, M пd Huпter, T r kl r l m 1 1 1 Х Te teriп, C, v п der Meuleп, M, Oppedi, B, de Boer, H, Hei ov r Di tr, S, Ki пe, W пd W пg, M D r l r 14- - rm rm rl m r i 1 1 1 Х Till, H, looglu,, Fr п er, M, Bi hop, S M, Koh п i, пd Hu rd, S r ll r l l m l r r r k i 1 1 Х Trotoch ud, E, H o, T, Wu,, Y пg, пd Cl r, S E A AA1 r r l k k r r A AA r m l ll m l l A R -r l r 11 Х erveer,, Wouter, F S, eyпold, пd B ti eп, I H Q m l r l r 1 r r l r l m m m r i Х W пg, Y, Seto, H, Fu io, S, Shigeo, Y, Chory, R 1 r l m l m -m m r r r r l r 1 R l l r Х Wiley, H S пd Bur e, M R l r r r k ll r k i 1 1 Х Willi, W, Wil oп, M пd Meyero itz, E M A l r l r k - r i i A AA1 ll i 1 1 Х Wu, K, Lu,, Sehп e, пd Ferl, r l r m l 14- - r r r m r r m r i i Х h пg, X -r r r r-l k k l i 1 11 Х Wy eпg root, L E, B iп, B, Oпg, S, Toпg,, oп, T пd Sicheri, F r r l r 2 r r r k r l j m m r r 1 Х Xi o, B, S erdoп, S, oпe, D H, Dod oп,, Soпei, Y, it eп, пd liп, S r r 14- - r m l r r m l l ll 1 1 1 Х Y e, M B пd Eli, E H r / r - m i i 1 1 1 1 Х Y e, M B, ithiпger, K, oliпi, S, C roп,, it eп,, Le er, H, liп, S, S erdoп, S пd C пtley, L C r r l r 14- - 1 1 1 Х Y lov y, S, odrguez Coпcepci п M пd rui e, W m r l m m r i Х v п ei l, M, Te teriп, C, Ki пe, W пd W пg, M ll l r r r l l m rl 14- - r Chapter e rch or proteiп iпter ctiпg ith the iп e do iп o SE K1 y ye t t o hy rid creeпiпg Iпgrid M ieпtie пd S cco C de rie r tr ct R r-l k r k R r k l m m l r m m r R r-l k 1 R 1 R l -r r R 1 r r l r l l m r l m r m m R 1 l r r m l k r r - r m r r r r k m R 1 A r l r r R r r r r r 14- - r AAA-A D 48 R A r R m r r r A1 r 1 r m -l k r 14 D R r l R 1 i i - r r Iпtroductioп r r l m r r l r l ll l r r l r i - r r r r r r r r l - r m l r m l ll r m l k l 2 r rm - r r r k l r l l r r l D A l 14- - r - rm 4 m 2 2 r r r r i i r r r r R 1 l -r r r r-l k r k A 1 l R l r r ll R r-l k r k R r k l m m l r R r ll l r m r m m r m r ll l r l k m m m r R r-l k R 1 R l r l -r r l r m m r m l r - r k l 2 l 2 1 R 1 r r r r l r l l m r l m l 2 r rk R 1 r i i i i k r A l 2 l m R 1 ll m l - r m r r k m R 1 r R 1 r r r 14- - r 14 AAA-A D 48 R A r R m r r r A1 r 1 r m -l k r ll r l r r r r ll r r r r l R 1 A m r l l 14 D 48 ll r l r r M teri l пd ethod Ye t t o hy rid creeпiпg D l A - r m Or l r r r r R 1 k r A R 1 k m R 1k 2 - 2 RR m R 1 RR 2 -2 4 m r R 1 r m l R 1- 2 r l r 2 2 r r 4- Or l r l l A 42 r l l 2 1 A r r r rm r r r r A r l l m 1 1 Or l A r r r l A 1 r m r l r r r A r ll r r r l l A 1 r l A r l l m R 1 Or l A r r l r r 48 A r 1 r l 2:: A - r rm r 2 2- R 1k 1 1 R 1 1 1 r 1 1 l A l r 2 r r r 2 2- R 1k r rm 48 2 2- R 1k l m 18- Or l 18- 4 l r r r r A - r r r rm r r l m m l/r r r 8 m /m l r 48 r r r r l r rm r 2 2- R 1 RR 2 2- R A i i i r D A l r r r r m 42 r 4- mR A r m l r l 2 r m r l r r r m l 21 D A l l r r m l i r r r r R 1k r r 48 r r rm 2 2- R 1k 18- 4 r rm 4- D A l r r r l 1 81 r m r r rm A r m l l r r r r r r l m m - - r r l 8 m / l l r j r - r r l l - l r - - l r r rr l l r r 2 / l r r r r l m r l 4- l r r l m - r r 2 2- R 1k r m r m l k l r r r 2 2 l m r m m 2 2- R 1k r m r m r r m m r l 2 2- R 1k r m m r l l m m r r l r r r r r r l r r r r l m A m r rm r R 1k r 48 l 2 2- R 1k r m r R 2 r 2 2- R 1k r 2 2- m - - D l r r rr l l r r l r r r r r r l r R 1k m r l m 4- l m r l l r r l l D A l l r r i r 8 r i l 4- l r r l m r r m ll l 4- l m D A r r m i r r r r r r R 1 4- l m r R 1k r r l 1 r r rm r 2 2- R 1k 2 2- R 1 RR r 2 2- R 1 - - l l l r r l r r A m r l r m l r r R 1 r r D A l l 1 1 D A l r r m i i l l R r r r R 1 l R 1 l 4- r l 2 2 m k r m 21 D A r m 1 4 D A r m 124 R 118- A1 28- 18 r l r m l R r m rr l l m - r r r m r r - AA AA A - - AA A A - r r r m r l l m - A A A A AA A - r m r r rr 2 4- roteiп e pre ioп пd iпity puri ic tioп r R 1k 4- l m l r m - r l r r D A l r l l r m l - - r r m l r D A m l 14 m l r m D A l 1 1 l m l r m r r r r 14 - AA A A A A A - l r m r - A A A A AA A - R r m l rr r - rm A 2 D A r m D 48 4 - D A r m 1188-24 r m l R r m rr 4- l m 4- r r m r r r r r r m r - A A A A - r r r m r -A A A A A A - R r m r rr -41 l- 2 l l 4- l m 248- r m R 21 - A1 2- 18 r r m 4 r l r r r m r l l -41 2 2 4- - A1 2- r l 244 r m r r m 248- r l l l- 2 2 2-r m 2 2-R 21 - r r r m r l r r l- 2 D A r m R 118- A1 28- 18 r r m k - r r r l r 41 r l l- 2 2 r m r - r r r m 2 2-R 118- 2 2- A1 28- 18 r l r rr l- 2 All l m r r r rm i 21 r r r r r - r m r l r r rr ml 2 m m ll r ll r OD r r r l -D l r r 1 m l r r r r r r 4 r ll r ll r r - r l l r r 12 l l - r r r r m r r m r l r 4 rm r m r r r r r l r m r 1 m l m r 8 1 m l - 14 r r r r m r l 14 r m l r 4 r r - r ll r r m m 2 / l r r r m ll r ll r r l m r 2 m r - l 2 m l 1 m DA 1 m D l r r 12 l l - r r r r m r m l r l l r r l r m r 1 m m l l m r r r r rm r r m r - -R A r ho phoryl tioп y r r l - r D A l l - r - r r - R 1k k r 2 m 1 m l 1 m l2 A 1 - 2 A l l m A r r - m r D A m l r r m 1 r 12 D A l m r ll l r l l A r r r l r m r m Q r r m l l r D m R 1k - r l - - r A R 1k e ult Ye t t o hy rid creeпiпg A A r - r m r r k m R 1 R 1 k m R 1k 2 - 2 r r l r 2 r l l A A r r l r m r r rm r 2 2- R 1k l r rm 2 2- R 1k m l r r r r r A r r r 2 2- R 1k r l A r r r r l 2 2 R 1k r l r r rm r r r m r r R 1 r r RR m R 1 RR 2 -2 4 l l 2 2 r l r 2 2- R 1 RR l A r r r r m r R 1 r m l R 1 1- 2 l 2 2 r 2 2- R 1 2 2- R m l rl 2 2- R 1 RR r RR m r r r i i D A l r r r m l r l r rm 2 2- R 1k 18- 4 r l 1 81 r rm A r m l 1 l r l l l l r r r r r A r r r r 1 8 l r l r r r l l m r 4- l r r l m r r ll r r rr l l l m r l 4- l m - r r l r r r l r m l m l m 2 2- R 1k r l m l r r l r r r r 4- -l r r l l A r r r l r r l r 1 m l r r l rr r l r r l r l m r m m r R 1k r l l 4- -l r r l m r r r l m r m r 2 2- R 1k r 2 2- m 2 l r r l r r r R 1k ll m l 12 l ll 4 - l m D A l l l 12 l l D A r l r 1 l r l rr r r m A r 11 l r k l l r r r m l r r r k l /r r /l / l m / r r rk ml 14 l r ll l 1 l r l r R 1 r r rm k m R r r l r r r r R 1k m r R 1 RR R 1 All r r r k m r r l r RR m R 1 r l r r l m ll r r r R 1 l l r m l r r l / r rr l R 1 r l l - r r k m R 1 r l l l D A l r R 1 r r r п ly i o put tive SE K1 iпter ctiпg proteiп l l - r l r r 14- - r 14 AAA-A D 48 R A r R m r r r A1 r 1 r m -l k r l 1 r r l - r l r r r 14 ll l - r D A l l - rm l r R 1 r r All r l 14 r l r r r m m r m r l r l r r m l m r r r l r m -l k r r m r l 1 r r -l rr - r l r l l l r r ll r r r r R 1 r m r r r r l l 1 ll l l - r l r l 14 l r D 48 2 l r r R 1 ll r m r l r 4 l r mm r r r 1 r r r r r r r r r r - r l rr r I 1, I 141 пd I 18 eпcode F r - r l r l R12 R141 R 18 ll m l r 14- - r 14 r 1A R141 k r r l 14 l A 12 r m m i i D A l 1 1 r R 4 m l I 55 пd I 146 eпcode CDC - r l r l R R14 rm AAA-A D 48 1 R k r r l D 48 l A 8A24 r m m A l r T le 1: O r l - r l r m r r r r l - r l r r r r l m r r l Ye t t o hy rid cloпe roteiп EST cloпe l R l R l A A l l m l m r m r m r l l R 2 2 1 4O24 22 8 D 48 112 R 14 2 18 2 14 R 2 4 1 R 11 4 1 82 R m - 1 12 A 1 42 AAD l k r R 1 2 4 1 82 RA - 8 A 8 2 R 1 4 1 A 4 2 A 2 8 2 R 1 2 1 AA 2 8 4 1 411 A R 1 4 144 R AA 1 4 1 22 8 42 R 1 244 2 A1 AAD 11 1 18 124 18 44 182 R 12 1 1 R 141 1 1 248 14 AAD 1 81 248 1 1 R 4 1 1 R 18 1 1 r m r i i D 48 18 r 2 1 4O24 r 22 r r r r l I 1 4 eпcode put tive N iпdiпg proteiп - r l R1 4 - rm l 144 r k i i r r 1 r l A Q r m m A l r m r r r 1 r 22 8 - rm l 2 r r r r l l l A r r l k r m l R A r i i l r R A r A-l k r r _1 48 m r l m l r r k r R A r R r r l m l k r m l m A r m l 12 r l l m r A- m r r r m r : m rm A m r l rm r - r k r 1 8 R A r m l l r - m l r r m m r m R A r R r l m m r / r l- l l r r m m l l l r l r r l r l R A - r l R1 4 - rm l 144 r R A r R 21 - m l r m r R 1 l k l r I 190 eпcode the K+ e lu пtiporter KE - r l R1 - rm l 2 r i i - l r r A1 1D A1 l A r m m 1 A1 r 18 r l r - r r Figure 1: m r R 1 r r : 14 B D 48 C R D A1 E 1 F r m -l k r Dr r r r l l - r l 2 = r m m r m rkA- = m r r r AD- m r 124 18 r 44 r 1- 18 A1 A1 1 r r r l l r l A1 m m r / - r m l m A r m l A1 l / r r A2 4 l k A m l : r r r m l 2 A2 m l m m r r l m l r -RO: 81 i l -r l m- l m r k / r r ll r l 1 / r / r r l r m l - m m l - m l r m r r r r r r l A r r m ll r l l A l lm r 2 1 - m r l r l r r r l m - l - m r r r r r ll l l r m m r m rm l m l r r l l m m l r l A k - m A1 A -l r 1 - 24 m l l r m m r m l m - rm l l A1 rkA- m A 22 4 r 422 m l AD AD m r r r l m l r r r r r r l r l - r l R1 l - rm l 2 r A A1 2- 18 m l R 1 r l k l l m l 2 r I 1 6 eпcode the put tive qu poriп SI - r l R1 - rm l 2 r l i i r r AA 2 8 4 24 r r l A 12 r m m A 4 r A 2 8 1 411 r A 4 r r l 1 - r D A l ll r l l - r r l r l l r m l j r r r m r l k r m A r m l 2 - m r ll r r r r : r r r rr r r r m ll r l l l r l l r l l r m l r l m r m m r m r l - m r r r m r r m l r l r r r l 1 k - m r l r l m m r - r r r A -r -Al A m l lm ll r r r r r r r l 1 8 l r r m l m r m l m m r 1-2 m ll m m r r l r 1- m l 2 1 r r l r AA 2 8 1 - rm l 2 r r R1 1188- l l r m m r m - rm l l m l m l r R 1 k m m l k l k l - rm l l m 1 r I, I 11, I 1 пd I 196 eпcode r ce e li e proteiп r - r l r l R 2 R11 R 1 2 R1 ll - rm l 82 r - l r m -l k r r 248- R11 k r r l r m r m -l k r l A 1 r m m 11 1 11 82 1 11 11 211 2 r r m -l k r : 1 12 r A 1 l r j r r 1: 11 8 -11 4 RA - 8 r A 8 2 l l m rk l 1 r l r r k r l r m -l k r r r m m r r - l m r m m l r r AAD i i m 2 r m m r m l m A r m l A r 1 1 1 l m r m 1 1 r l r r l r l m r r l m r r l r m r r D- r l m r m r r r D- l m m r l l k l l r r l ll ll l r 2 eri ic tioп o the iпter ctioп iп ye t ith EST derived peptide corre poпdiпg to the put tive SE K1 iпter ctor r - r r rm r l r l R 1 r r - r r r r r l m ll - rm l r r r r l rm ll rm m l r r r R 1 r l r l l l r r R 1 r r r r r R 1k r r 14 m l r R 1 r r - r r All r r r r r l r l m l r 1 lr r l r r l r m m r m rr ll m l k l r r r r l r r 1 r r R r m -l k r r r r m l m rm l r r - r l r r r r R 1 r r r r l r D 48 r 4 R A1 1 l r R R 118- 1 l r r 124 18 lm m l A1 r A1 1- 18 1D r l l m l l r l r r m m r m A1 28- 18 1D l 2 r R A1 R 1 k m r ll r R 118- l r - r r 2 2 m r ll r - m l l k l R 118- 2 2 l r r r rm r l R 118- l r r 4 r R 1k l 14 D 48 R A1 r m l k l l r r R 1 k m r m l k r r 1 r m l r r r r r r r r T le : r R A1 k m R 1 rm R 12 - 1 A1 28- 18 124 18 - r m l r rm R 1 r r r 2 2 = r AD 4- = r r AD m r r r R - r l r r r -/ r r - r ut tive N iпdiпg proteiп KE B AD-R AD-R D-R AD- A1 AD- A1 D- A 21 - 118- 118- 2- 18 28- 18 28- R 1 - - -/ - - - R 1k R 1 RR - - -/ - - - m - - -/ - - - SE K1 iп e tr п pho phoryl te put tive SE K1 iпter ctor R 1k l r l l r r l r r l 2 1 r r r l r r rm r r r R 1 r r r R 1 k m r r l - - r r k rm m m r l r 248- D 48 4 -8 R 21 - A1 2- 18 1188-24 r m r l - r l r m l r l r rm r i i R 1k r r l - R 1k r r - r r l ll A 2 O l 14 D 48 4 -8 R 21 - r r r l R 1k l 1 4 R 1 r r l r 2 l - Figure : r r l R 1k r l A r l r r l r m r ll l r l l A r r l r m r B 248- B:

- R 1k - D 48 4 -8 L пe 1 -r m L пe 188-24 L пe -R 21 - L пe 4 - A1 2- 18 L пe 5 14 L пe 6 L пe L пe 8 r r l R 1- r r r k - r r m r R 1k r l m m r r r l R 1 r r l r l - R 1k r r l 14 l r r r r l R 1k r r m 14 r m l r r l 14 D 48 4 -8 R 21 - rm - r R 1k - r l rm - r - r l ll A R 1k r l l 14 D 48 r r 4 r l r R r r R 1k r r l R 21 - r r l R 1- R 21 - r l R 1k r r l l r r l r R 11 - 8 - r m r l r A1 28- 18 - r r r l r l l R 1 r r l 14 D 48 R i i A1 1 r m -l k r r r r l R 1 r r r l r m r r l Di cu ioп Short de criptioп o re ult - r m r r r r r ll l r m R 1 r R 1 r r r 14- - r 14 AAA-A D R A r R m r r r A1 r 1 r m -l k r 14 ll-l r r R 1k D 48 R A1 rm l r - r r r r i i D 48 R r r l k R r l l 14 D 48 R l r l R 1 ll r Figure : r r l R 1k R - r l D A 1 A r l r r l r m r ll l C r l l A r r l r m r B D B L пe 1:

- R 1k R 21 - L пe :

-R 21 - L пe :

- R 1k -R 21 - C D L пe 1:

- R 1k -R 118- L пe :

- R 1k -R 118- - r r T o hy rid creeпiпg;

detectioп o l e po itive - r r r r l 1 r r l m r r r r D A m r A D r r r r l r r r r r m 42 AD r r r O r r r 2 A r m r 48 r r r l A l l m r l r r r l r l r r ll r r r l r r l m r 2 r r r 48 r AD- r r kl A D- j k l 1 l r r r l r r r r r l R 1k ll rk l r r kl R 1k ll l r l l - ll l ll r l r r j k l 1 r r r l r r r r r l r m l r l r r r l r m r r r r m l l r r r m l r l k l r r r r r l r m l l r l r r k l 2 r r r l r m r r rm l m l A D-l r r r m r r rm rm R 1k r l l m 1 8 l r rm l A m r r r r ll l l ll r l l ll l r 1 r r R 1k r r r l r kl l ll l m r m 12 l r l m l l r r r l r r rr r r m r r ll 2 r r r r k r r r A r m l r r r r r r l A- r r r lm r A r ll 2 r r r 48 m l j k l Al R 1k l l r m l O 12 l 12 l r R 1k r r Al l ll ll l l m r r r l r r r r ll k r l l l l r m r r r r - r r l - l r r r k l 2 r ll m k r r r r l r r l r l r m R 1 RR l r r O l R 1k r r r m R 1 RR r l l - l r l r l l l r rk l A m r r m k r r r - l r r k l m 2 - r r r l m r r r r ll m r l m m r 1 4 r ll l r r r r r l m m r r l r rm l R l r l r r r r r r r m r m r r l r r r r r r r l r ll r ll r ll l m r r r m r r r l r r l m r l r r l r r r r r k l 2 ll r m ll m r m r m l r m - l l - l l r r r m r - m ll r ll r m ll r r l r r r m m ll m r - r r r r k l m 2 r r l m l r - l r r m ll r r r l r rm R l - l rm m l l r mm m ll ll r r l r r l r m r r l l m r rm ll m k ll-l r r r r m D A l r r 2 2- R 1 m r l r l l l - rm l r -44 k r r AA 2 18 l - rm l r - 4 m r AA 242 l r r k r r m r r r r r R R 1k r R 1 RR l r r m k l l k l r r l ll r l r r r R 1 rm r l r r D 48 R A1 - rm l l A1 A1 28- r r r r A 4- - A1 28- r r r r R 1k r r A1 l m l r m -l k r r 1 r l l 1 m l l r m m r m l r m ll r ll l r - rm l l D l r l m m m r r ll-l r R 1k r r r r m -l k r m r r m r r r r m r 1 12 r l r r ll 4 l - r l l r m r l rr r m m r m r r m - r D- r Am r D- r l r r r r m r R 1 r r r l 14 D 48 R A1 ll l l r r r l R 1k r r r l r r rm r r r R 1 r r r r l R 1 l r l 14 D 48 R A r r r r - r l r - rm l l m l A1 28- 18 l r l R 1k r r r r l r R 1k A Biologic l igпi ic пce o the poteпti l SE K1 iп e iпter ctor m l l r R A r A r l R 1k r r r r l r R 1 r r l r r l R A r l l l l r r l AA - r r A 1 m l r l r R A r A/ r - r k AA l 2 2 AA - r l r r r r A 1 mR A A 1 AA r l r r R 1 r m m r r r r m k l R 1 r r l l r r r R l r l l l r r ll l r l l R r i i r R 1 r r rm r R l R 1 r r r R 1 r r 14 D 48 r r r r m l r A r l r R 1 l 2 2 m r r 1 r 14- - l - r m mm l D 48 m l r l r r rm r m l l r i i l r 14 r D 48 r r - r r Coпclu ioп l - r r r l r l l r l l m r r m r mm l r m l r r r r r r ll r r l r r r m l m r m l r r i i ll- i i rl r r m - mm r r m l l r r r l l r l l ll r k m l r r r l rm r k r r r r l r m j r r ll l r r - r m l l ll r - r r r r k l r - r r r r r l ll R 1k r r r r m kl r r l m l r r l r m r r r k r r m r - r l l m r l r r r l m m m r r r m ll m r r l r r r r l r r r l - r r l k r r m r r r m l l r r r m m r r r ll r m m r r r l r m r l m r l r 1 8 l 2 r r - r m m r r r r R r r r r - r r r e ereпce Х el eп, K B пd l greп, M r r m l - m i i i 1 Х Bu u, B пd Hor ich, L r m Х Col, пd Breпt, m - r r l m l i 1 Х Ch u oпt, F, B rrieu, F, Wo ci, E, Chri peel, M пd uпg, A r l r l r r m l i 1 1 1 Х E to,, Breпt, пd ole i, E rr l - r i i m r m i 1 Х F heп, S, Sere rii, I пd ole i, E l - r r r : r r r Х Fiпley r, L пd Breпt, - r l r l r rk i i i i Х Froger,, T llur, B, Tho, D пd Del rche, C r l r r l r l r i i 1 1 Х l v, S пd T ппer, M E A r l m r m i 1 Х re e, M, de,, Steiп пп, T, Kieпtz, M, h eld,, S lchert, K, Koпcz, C пd urgeп, A r m i i O r m r l l Х yuri,, ole i, E, Chert ov, H пd Breпt, D 1 m r k2 1 Х Hecht, ielle C lz d, H rtog M, Sch idt E D L, Boutillier K, ro пi l u пd de rie S C i i 1 r l l m r m r m l r i 1 1 Х I ed, Y, Koizu i, N, Ku пo, T пd S пo, H 14- - r r l 4 1-r l r k 4 r l r r i 1 - r r Х Li,, Kiпo hit, T, пdey, S, Ng C K Y, yri, S, Shi z i, K пd пп, S M l R A- r - - r k Х Miller, S, Dougl, M, C rter, пd Booth, I l - l m i i i i Х N, K H пd Li, R 1/ A 1 r r k r m r r ll Х S ier r, M H, Eпg, B H, F rd, S, rg,, H ggerty, D Hutchiп oп, W, c, D L, L i, E C, Liu, H, Nu iпe, D, O r, M, o, S S, ul eп, I T, u п,, Sli iп i, M, T eпg, T T, W chi, S пd Youпg, B l r r l r r r m l r l m l i i i 1 1 1 Х Schlo er,, H пп,, Bo e eyer, D, Schпeider, E пd B er, E AD i i i - k r rkA m l r rkA m m l r r l r AD r l r r i i Х Sere rii ii, I, E to,, Ber п, M пd ole i, E A r l - r m i i Х Sere rii ii, I пd ole i, E l : l l m l - r m i 1 Х Sh h, K, dell r, T W, v п Erp, H, Hecht,, пd de rie, S C ll l r l l l m r i i i m m r R r 1 r i 1 Х Sh h, K, u iпov, E, dell r, T W, Wille e, пd de rie, S C i i k - r r l r l m m r r r k 1 1 1 Х Sh h, K, ervoort, пd de rie, S C R l r R l - r - r l i 1 1 Х h пg, S H, Liu,, Ko y hi, пd Toп, N K ll l r l r / D 48 r 4 1-r l r r 1 i 1 1 1 Ch pter The So tic E ryogeпe i eceptor li e Kiп e iпter ct ith the 14 proteiп F Iпgrid M ieпtie, ered z, п Wille Bor t, Eugeпi u iпov пd S cco C de rie r r r r R r r Dr j l A rl m r l r tr ct -r r r m m r r r-l k k r m r m l l r m m r R r-l k 1 R 1 R l -r r R r r l r l l m r l m A r l - r r 14 m m r i i i m l 14- - r r k m R 1 ll- R 14 r r ll r l R 1 k m i R 1 l r r l 14 l ll r R 1 14 m r - mm r rr R l r l l ll R 1 14 r R 1 r Iпtroductioп r r l l r r l ll l r r R r-l k r k R r k l m m l r r ll l r m r m m r m r ll l r l k m A l r m l m l R l -r r RR r m m r r r RR m l l m r - r r r r r m l l D r 1 4 r r m r r l r r l l i i m r 2 RR-R r l l l r k A R m l 1 21 r l 1 r m l RR-R l r RR r r k r r r l ll l r r m r l m - m l 2 1 r l r l rm l k l RR r r k l 2 2 m r r r m r R 2 r l i i m m r R r l k 1 R 1 R l r RR l r m m r m l r - r k l 2 l 2 1 R 1 l r l r m r r m l m l l r l l r l 2 1 r R 1 r l i i l r m m r rm l r r r l m m r rm R r r r r l r l l m r l m l 2 r l l m l r m r l l - ll l m - mm r r m r r r i i l r m l r r r r R 1 l r 2 1 r A AA r l 1 l i i r r R r r R 1 RR-R R l r r l r l m l 2 1 A l l m R ll r r r R 1 l r l R r r l rl R 1 ll l 2 1 R ll r R 1 l k l k 2 r r 2 ll m l R1 r l R 1 R 1- - r r l r l r l R ll m R r r l 2 2 l 2 2 2 l r l R r l R1 r r r m R l RR R A 1 R 1-A r r 1 r r r R 1 r r r ll r r l 2 m 2 2 A 1 m l R 1 l R m l m m r R r A 84 RR-r r k A 1 R 1 i i i i r l r l k l r r r m r m R ll i i l 2 i i r l m r m m l rk l 1 l 1 r l 1 RR-R rm m l 2 RR r k m 1 r m l 18 kD 4 kD r l 1 rm r m l r m ll r r r l k - r A r l r 1 R -r l r r l r 4 kD r r m l m R 1 ll m l r m l k r rk R 1 r i i i A l r l r l R 1 l 2 l m R 1 ll m l - r m r r k m R R 1 r R 1 r 14- - r 14 i i i i / 14 R 1 r k l ll m m r 14 R 1 R 1 k m r l R 1 l r r l 14 i i M teri l пd ethod Ye t t o hy rid creeпiпg D l A - r Or l m r r r r R 1 A i i i r r D A l r r r r m r 4- Or l mR A r m l r l 2 m r 4- 88-r i 42 l r r r m r l r r r m l 2 1 D A l l r r m l i l k m R 1 k r A 82 2 - 2 l r 2 2 Or l r r A l 2 1 ll r l r m r r rm r A- R 1k l : r r A- R 1k r r r rr l l 2 r A R 1k r m l r r r r D A l r r r rm r 48 A r r A - 2 2- R 1k r r r l m 18- 4 r rm r l 1 8 1 l A r m l r rm r l l l 8 m / l l r j r l l - l r l R 1k l - l r 48 r l l l 4- l m l r r l 18- l m R 1k - r r r r r m r r 4- l r r l 2 2- R 1k r 2 2-l m r r l l r r r R 1k m r r r r r l 4- l m D A r r r O l r r r _ 822 14 R 1 r l r R 1 k m 2 - 2 r r m r R 1 r - rm l l R 1 1- 2 m r R 1 r ll l r m R 1 RR 2 -2 ST u ioп proteiп e pre ioп r r 14 14 -248 A R 1k r l l r m l - - r r D A m l 14 m l r m D A l 1 1 r R 4 i i l l R r r l m l r m r r r r 14 - AA A A A A A - l r m r - A A A A AA A - R r m l rr r -41 rm 4- - 14 -248 l m r l r m r r m r l r -41 l m - 14 - 14 - - R 1k m r -41 r r rm i r 21 r r r r r - r 1 m r l -D- l r r r l l r r l r 4 ll m r r r rm - R 1k r r l r m 1 m r l m r 1 m l r l m r 4 1 m D m DA - 14 - 14 -248 r r r R 1 r r r m r l 14 14 -248 r m l r 4 r r r rm r r m r - R A r roductioп o F14 пd SE K1 iп e пti odie 14 r r mm r r ll l 14 r - r r m r r m r r l r r m r mm l r l r r 14 r m 1:1 l r r l r m D -A l l r r r r r 14 r m l r r 14 r r l r m l r ll R 1 1 r r r r r D A r 8 rr m r - RR m R proteiп iпdiпg y ll- 14 R 1 k m R 1k r r rm rm r - r r r l - r l - R 1k R 1k r l 1 A r m l l m r r : 2 m 1 m l 1 m D 1 m DA m l2 r R 1k l r 4 r m r m m r r A r r - R 1k r r l k 1 / k mm m lk 1 / r -1 2 / A / r -1 r m 4 r 1 14 r 14 -248 mm l r - R 1k r r r m m r r mm l r m l r r m 1 m r r r m r m D -A m l r 1 r m r r r r 12 D -A r rr r ll l m m r l r ll ll r l r m r r l r l lk l m r ho phoryl tioп y r r l 14 14 - r r - R 1k r 4 m r l r 2 m r 1 m l r 1 m l l l A 1 - 2 A l l m r D -A m l r r m 1 r r r 1 D -A l m r ll l r l l A r r l r m r m Q r r m l l r D m I uпoprecipit tioп o F r r r r m i i i ll rr 2 2 r r r m m l 1 l r l m A 1 r -1 r r 1m 1 r 1 /m l r m DA 1 m r - mm r 2 1 R r 14 r m r - r A l r r 4 r 1 -2 r mm - m l r l r m r 1 r - 1 l m m l r m r 1 r 1 1 l ll l l r m r 1 r mm r r r l r m r m l r 1 r m r r r 12 D -A l r l 14 r m l r R 1 r r l r rm r r r - m Am r m r r Loc li tioп пd iпter ctioп o CF YF u ioп proteiп iп protopl t D A m l 14 m l r m D A l 1 1 l m l r m r r r r 14 - AA A A A A A - l r m r - A A A A AA A - R r m l rr r O r l - 14 r R r m l l rr r 1 l r l r -14- - r m l r r l - 14 r r r R 1k - r r r l l 2 1 - 14 - r l k r r 1 l r r 14 r R 1- r l k r r All / r r r r r l r m r / r r r l r i i m ll r l r l r l r l l l m r rm r ll l r l r l l r r 1 l m r rl rm All m r m m r m r r rm r r l l 2 2 r DA r l r r 1 m - r l 4 r rm l r m - r l r l r 1 /m DA 4 - -2- l l l l r r r rl A A l - l r m r D- m r r r k DA l r l r r A l m r l r R r r r R l r l l ll R 1k 14- - r m r l r r l m r r l 2 2 r l m r r l mm r j 1 r /mm r r l r r r l l m l 1 m rr m j l l r D r m r r l l r r r rr r k r l r m r k r r r ll l r r r m m r l m A r l A r 1 r rm l l r r r l r r -1 l r r 14 m m r l r k 2 m r l e ult F14 ct ith the SE K1 iп e do iп iп ye t iпter r ll r R 1 l 2 - r D A l r r r m i l r l r k m R 1 2 - 2 R 1k r r m l 1 r rm r l 2 l - l l r r l r m r r rm r m l A r l l r r l R 1k r r r r 12 l l R 1 r r Am r r l m l 14 m m r i i m l 14- - r All r l r l r r r m m r m r l r l r r m l rl r r m D A l r r m r R 1 r m l R 1 r l 14 m r l r l l l k - rm l 8 r 14 -248 - r r r r rm R R 1 r r 14- - m l m m r r l r R 1 r l r m ll l 14 r R 1k kl r R 1 r R 1 r ll l r m R 1 RR r l l r rm r r l r r m 14 - r r r r A l r r r 14- - r r l r 14- - r 1 r k r 14 R 1 m r r 14 R 1k m rr l m l R 1 m m r r l SE K1 i le to tr п pho phoryl te F14 ell F14 9 r r m r k 14- - r r l 1 4 r l 2 r r r r r R 1 14 r l r r rm rm r R 1 14 r A r r r l 2 :// k/ r / r r r r r r l - rm l 8 m 14 r R 1 l r l r r mm r m l r l 2 1 - rm l m 14 r r m r r l r r rm r R 1 l r r l r r l r r r 1- 8 r r l R 1k 14 14 -248 r r - rm l r l - - r r i r r m r l r l r m 14 r m r - R 1k 14 r m l l r m 2 kD kD 1 kD r l r 1 14 - l l m l l r m 24 kD l r r 14 28 kD r Figure 1 O r r 12 D -A l m r ll l r r r i r l l l - - r r r r m r l r l r m 14 14 -248 r m D -A r r m m l l r m l 14 r r r l r r rm 14 14 - r r - R 1k - 2 A r r m l r m l r j D -A r r r l r r r l - R 1k r r l 14 -248 m r l k 14 r l R 1k m r R 1k r l m r 2 r 1 m l2 R 1k r l m l m l 2 1 m - r l 14 r r l R 1 r l R 1 r Figure : i r l 14 14 -248 - R 14 14 -248 r r l R 1k r r A - 2 A L пe 1:

- R 1k 14 L пe :

R 1k 14 -248 B: m r - R 1 14 r l r r i i r l r r 14 r l R 1- r l r r 14 r 14 -248 - 2 A R 1k r l r l R 1 l r l 14 r l r r - rm l r F14 ct ith the SE K1 iп e do iп iпter k m R 1 14- - m rr r- 4 R Q r r 14- - r 14- - m m R r r m r l m l l 1 l 1 k l 2 2 A r m l m l R 1 k m m 4 l 2 Figure m l m l k m R 1 k m m l r r r 21 m l l 2 14- - l l r m k l k k 14- - r m rk rr R 1 r m l k m l r r r r l 1 4 A r m l 14- - R 1 r l r m k m m l r l r r l 14- - m 14- - rl l rm r r R 1 ll- r r rm r l ll- m l - R 1k 14 r r 4 14 r R 1k 4 l 1 l 4 l r l r r 14- - m m r r r 14- - r l l 1 l 1 r r ll r m r l R 1k r r rm r r l R 1 r 14 R 1k r l r A r l A r l R 1 k m r - R 1k r r - 2 A ll r rm ll-l 14 r r l R 1k r m r 14 r l - R 1k 4 l 2 m r - r l - R 1k 4 l r m r r l m r 14 r l R 1 l r m r - r l R m r m r r r 14 -248 r r l - R 1k r 14 r 14 -248 r l 4 l 1 ll r rm r l - R 1k 4 l 4 r r l 14 -248 m r - r l - R 1k l r m r l l r r l - r 14 R 1 k m ll r l r r l - r r r r m 14 r r Figure 4 ll r 14 14 -248 k m R 1 14 mm l r - R 1k r r r ll j D -A r l 14 r m l r 14 R 1k L пe 1 : ll - R 1k 14 r r l r l L пe 4: ll R 1k 14 -248 r - r l r l L пe 5: ll F14 ct ith SE K iпter R 1 l r l r m r r m l m rl m r l 2 1 r l l r O r r r 14- R 1 r i i r R 1 r R- R l r r l r r 14 r l k l rl R 1 r r r R 1 14 r i i ll l r r m - l r i i ll rr 2 2 r rm mm r R 1- 1 r 14 r m 14 r 14- - r R 1 r - l r i i ll rm r l r m l 1 14 r m r r m r r r m m r 14- - m l 14- - r m l i i r l l m l l r r r m 2 kD 14 14 1 kD 14 R l 2 mm r 14 r m r r rr l r m l l r l 1 l 2 r l r m l r m m r i i 14- - m l r r l r m l l r r l - r R R 1 1 l r m r l l R 1 m m r 14- - m l i i m r Figure 5 i r 14 R 1 L пe 1: D r r l r r l r m l r i i ll 14 r m r 14- - r r mm r mm l r m r R 1 1 r r mm - m l r ll j D -A r l r m L пe : mm r 14 r m L пe :

mm r r r m m r i i 14- - m l 14 m ll m m r R l 2 1 r m m r 14- - m l 14 r r r m r r r r r r Co loc li tioп o SE K1 пd F14 пd coп ir tioп o the iпter ctioп rr i i r -l l R 1 l rm ll l r l l l r l r r r 14 - rm - - 14 r r R 1 - rm R 1- r r r l r m ll r l l r r m ll r r r l l l r l r R 1- - - 14 - - 14 r R 1- -j r R 1- r l l r l l m m m r l r m m r l 2 1 r rm r l l R 1 r r - 14 l r l l l r l l - 14 rm l l - 14 l r DA k-m 14- - r ll l r l l l l m r ll l r r m 14- - r r m l i i rm l l m m m r r l m l r l r m k l 2 2 m ll l r l l R 1 r 14 - r 14 R 1- r l r m m j l l r l m m m r r l l r r r - r rr m l l r r R 1- - 14 m r l r R r r r R r R 1 r Figure 6 ll l r l l l r l l ll R 1 m ll r l All m r l r r l r ll - l r r l r r l r C: ll l r l l R 1- r m m A r l D F: ll l r l l - r m m D r l :

-l l R 1- 14 r m m r l K M: DA r l l l - 14 l r l m r l r m m r l r r l r r R r l r r r l - l r l l l r m m r R l r ll l r ll r m l l r r r r l r r R m r l r r l m r m r l m r k r m m ll r r l - r R 1- - 14 r m l l r l l l r m r r r A r l r l m r k r m r l r l - 14 r m r l r r l k 48 m rr m k 2 m l r r 48 2 m m r R r r m r r m r m m k 48 m rm l m r r m m r m r l ll l m m m r r r l - r R 1- - 14 l 1 2 m r l m r m r m 1 r l l r - 14 m r r m m r m l m m m r r r l - r R 1- - 14 r r l r 4 m r m r rm m m m 1 R r r r l l r m m r r l 2 r l l m m m r R 14 r r l r rm A r l A r 1 A r rm l l r r r m r l r k r r l l l r r l r r rr R - 14 R 1- ll r l r 48 m m l r 2 m m l l l r l m ll r l m m m r r - 14 R 1- -l l r r A r l l r ll r r r r l r R 1 r Figure R- R-A l r l r 14 R r R- l l r r rm l 48 m r m r m r r m r l - r R 1- - 14 r l ll r r r l m m m r r r B l R-A l r l r R 1- - 14 l m m m r C r ll l r r r D r m r r l r r r l l r l r r l - R 1- l r r 2 2 184 r l D 84 r l m r l r r l r r r l r r r r r l l r l r l r R m r m r r l r r r m l r l r l 1 r R 1- 14 R r r r r l 2 r l r R 1- m l l l r r l r r r ll r R r l r m m r l r r l r R 1 r r l l m m m r l ll ll r r Di cu ioп A - r r r rm r r m m r R r-l k 1 R 1 A r l r 14 m m r i i m l 14- - r r k m R 1 14 l i i 14- - rm r r - r r R 1 r R 1 14 rm i i ll mm r 14- - r - r R 1 r r i i l ll i i r rm ll l r l l m l l r r l r l l ll 14 R 1 l m m m r r l k r l r R 14 l 14- - r m l l r 28- 1 kD r 14- - r r r l r r k r l 1 r rm i i R l 2 1 r l 14- - r k m r l m- r k D 1 D 2 m l 1 8 r l 1 r r k 4 k l 2 r r r m m r -l r r k r r l 14- - r l r rm r r r l r A m l l l m m m r R 1 r -A 14- - - rm l m - r m rm -A -14- - m l l l l l 1 i i l m k D 1 m l 14- - r r - m l 1 8 14- - r l m r r r r r l r r m m l ll m l 14- - r r l m mm l ll r AD r r AD r m r m r l- m l r l r l m 14- - rm l l r k - - R -1 r l 2 l r l m- k D 2 r r m l l r 14- - l r l r r r l 1 r r 14- - 14- - k r 14- - r r r r r l l 1 14- - l ll l r r l r r l k l r l l r r l r m l r 14- - ll l r 2 m l r l 2 l r m r 2 r r m r r - r l 2 k r m l r r r l r r r - r r r 14- - r r m r 14- - r 14- - m r m R r r m r l m l l 1 l 1 k l 2 r l r r 14- - m m r r r 14- - r l l 1 l r m 14- - r l r m m m r r r r l r r O k 2 2 k m R R Q 14- - m ll ll-l 14 r l r l R r - m l l- r l r l R R 1k l r l r r l l r r r l 2 1 R 1 l A l r r r r r l r - m l r l R 1 r m r r r r r 4 14- - m r 14- - r r m l m r l 1 r l r r 14- - m r r l r m rm 14 - 14- - l 1 l 1 14- - m r rm r r - rm l m 14- - m m r rm m r r l r l - rm l m rm l m m r r l mm r r l r m r r l 1 r l r r r - l l m r rm r l r l r r rm r r l r r r r r r r r - rm l m r - l l 14 -248 r r l - r k m R 1 m l 14- - r A m l 14 r m r ll r r r r r l l r r r r 14- - R 1 rm 14- - m r m m r r m l r R 1 2 14- - rm r r m l r r l l r l r r r r r r l m r l r r l r r i i 14- - rm r r r m r - rm l l m m m r -A R l 2 R 1 l r r l r l m l 14- - 14- - rm k 1 r l r R k r l 2 r l l 14- - r r ll r l R 1 r i i 14 14- - rm r l m m r k l 1 4 14- - r l r l r r 1 8 r l 14- - r - r r l r rr r r / r r r r l r l l r r m R 1 ll m l R rm m m r l r l l 2 1 Al m r l R 1 m r R r l r m r l r 14 r r l R 1 m - r r m r c пo ledge eпt r r l r r m r m l r l mm m r k r l l r r l r m r l r l l r rm r l j r r Ol l k r r l r m r ll l l k k r r r r r r / l r rk r r 8 18 2 r m rl Or r R r O R r Q 2-2 - r m Q l m R r r r m R r 81 2 r m O R r e ereпce Х eпo e Iпiti tive A l m l r l i i i Х B ti eп, I H пd oviп, T M r r m r k r ll l r r l r r : l r -l ll r k i 1 Х C oпi, L, H rper, F пd l greп, M 14- - r l l m r k D 1 Х Ceпtury, K S, L g п,, d i oп, M, Morl п,, To i,, Sch rtz, K, S ith,, Love,, oп ld, C пd Wh leп, M C D l m l r l 1 m r r 1 Х Cl r, S E, Willi, W пd Meyero itz, E M l r r k r l l r l m r m i i Х Furl пetto, W, Dey, B, Lop czyп i, W пd Ni ley, S 14- - r r l r r r r l r r i Х ez ez, L, B uer,, пd Boller, T r ll l r l -r r m k 2 r r r r l ll ll i i 1 11 11 Х re e, M, de,, Steiп пп, T, Kieпtz, M, h eld,, S lchert, K, Koпcz, C пd urgeп, A r m i i O r m r l l Х He, X, eпdroп, M, Y пg, Y, Li, пd W пg, Y -l k k r l l R1 r l r r r ll i 1 1 1 Х Hecht,, ielle C lz d,, H rtog, M, Sch idt, E D L, Boutillier, K, ro пi l u, пd de rie, S C i i 1 r l l m r m r m l r i 1 1 Х v п der Hoeveп, C, v п der W l, C, uur,, v п Di, M C пd v п Blitter i, 14- - l l r k - R -1:

r l 14- - r l i R 1 r Х Hu rd, S, Wei, L, Elli, L пd Heпdric oп W r l r r r k m m l r r Х I ed, Y, Koizu i, N, Ku пo, T пd S пo, H 14- - r - r l 4 1-r l r k 4 r l r r i 1 Х pert, N пd Oec iпg, C R l r 14- - r l m rm l l m m m r -A r l m r 1 1 Х eoпg, S, Trotoch ud, E пd Cl r, S E i i r r-l k r r r r l A AA1 r r-l k k 11 1 1 Х Ko e, B пd Dei eпho er, l -r r : r l m i i 1 1 1 Х Korthout, H пd de Boer, l l m m m r 14- - m l r l l rm - m l i i Х Li,, Le e, K, T, F E пd W l er, C R 1 r r r l R 1 ll i i i i 1 1 Х Li,, Weп,, Le e, K, Do e, T, T, F E пd W l er, C A i i RR r r-l k r k r R 1 m l r r ll 11 Х Liu, D, Bieп o,, eto, C, Collier,, H l п, F пd Liddiпgtoп, r l r r rm 14- - r 1 1 1 Х Lopez iroп,, K пoh, пd u ell, l r l 2 r r r D A m k i 11 Х Lu,, Sehп e, C пd Ferl, r l l m r r i i 14 r r m l 1 1 Х M t u y hi, Y, Og, M, Morit,, S g i, Y A RR r r k l r l rm l k i 1 Х Meпge, M пd Murr y, H r i i l r r l ll- l Х Moorhe d,, Dougl,, Cotelle,, H rthill,, Morrice, N, Mee, S, Deitiпg,, Stitt, M, Sc r el, M, it eп, пd M cKiпto h, C r l - r m l m l m 14- - r 1 1 1 r Х Mu liп,, T ппer, W, lleп, M пd Sh, S r 14- - ll r m r r Х N, K H пd Li, R 1/ A 1 r r k r m r r ll Х ig glio, E, Dur пd, N пd Meyer, C A r m - rm l m r r r r m rk r l 14- - i 11 1 Х o ei,, iedr, S, h пg, D, Kle ig, F, Hirt, H пd oпe, D R A r - - - A k ll l r l :

r r l r l l r Х o eпqui t, M, l ter ord, M, L r oп, C пd So riп, M D m i i m r l 14- - r m r r l i 1 1 1 Х o eпqui t, M, Sehп e,, Ferl,, So riп, M пd L r oп, C l 14- - r m l : l r m r rm m l ll l r r m r l l Х Scheer, M пd y п r, C m r r R1 r m i i m m r RR r r k m l i Х Sehп e, C, DeLille, M пd Ferl, mm l r : r l 14- - r m l l- r r Х Sh h, K, dell r, T W, v п Erp, H, Hecht пd de rie, S C ll l r l l l m r i i i m m r r r k 1 r i 1 Х Sh h, K, u iпov, E, dell r, T W, Wille e, пd de rie, S C i i k - r r l r l m m r r r k 1 1 1 Х Sh h, K, ervoort, пd de rie, S C R l r R l - r - r l i 1 1 Х Sveппelid, F, Ol oп,, iotro i, M, o eпqui t, M, Ott п, C, L r oп, C, Oec iпg, C, So riп, M r l r- 48 rm l m m m r -A r r r l r 14- - r 1 R 1 r Х T п, Y, De eter, M, u п, H, Co, M AD r-1 r l r l AD/ l- r ll r l i Х Trotoch ud, E, H o, T, Wu,, Y пg, пd Cl r, S E A AA1 r r l k k r r A AA r m l ll m l l A R -r l r 11 Х W пg,, ood п, H M пd h пg, H A i i 14- - r r r l r Х W пg, Y, Seto, H, Fu io, S, Shigeo, Y пd Chory, R 1 r l m l m -m m r r r r l r 1 Х Wouter, F S пd B ti eп, I H l r m r r r k ll i 11 11 Х Wu, K, Lu,, Sehп e, пd Ferl, r l r m l 14- - r r r m r r m r i i Х Xi o, B, S erdoп, S, oпe, D H, Dod oп,, Soпei, Y, it eп, пd liп, S r r 14- - r m l r r m l l ll 1 1 1 Х Y e, M B 14- - r rk k r r l m l l r l Х Y e, M B, ithiпger, K, oliпi, S, C roп,, it eп,, Le er, H, liп, S, S erdoп, S пd C пtley, L C r r l r 14- - 1 1 1 Х Yiп, Y, W пg, Y, Mor rci, S, Li,, Yo hid, S, i, T пd Chory, m l l r r r r l r r m m l 1 1 1 1 Ch pter SE K1 receptor li e iп e igп lliпg iпvolve proteiп co ple coпt iпiпg CDC Iпgrid M ieпtie, o e ieп iп пd S cco C de rie m r l r tr ct -r r r m m r r r-l k k RR-R r m r m l l r m m r R r-l k 1 R 1 R l -r r R 1 r r l r l l m r l m - r r D R 1 r r i D 48 r r ll r l R 1 k m R 1 l r r l D 48 r - rm l 2 m r D 48 l l r R 1- r r A - mm r r l i i ll D m l R 1 14- - r R 1 r D Iпtroductioп R r-l k r k R r k l m m l r R r ll l r m r m m r m r ll l r l k m r l i i m m r R r-l k R R l r l -r r l r m m r m l r - r k l 2 1 l 2 1 R 1 l r r m l m l m rl m r l 2 1 O l r m r r m l m rl m r R 1 r l l r l l r r R 1 r l i i l r m m r rm l r r r l m m r rm R 1 r r r r l r l l m r l m l 2 1 r rk R r i i i i k - r A l 2 l m R 1 ll m l - r m r r r r k m R 1 r r r r l R 1 r r 14- - r 14 AAA-A D 48 R A r R r 2 r ll l r D 48 R 1 r l k m R 1 D 48 r 14 A l m mm l D 48 m l / r l A -2 k r l 14- - r l 1 l r M teri l пd ethod Ye t t o hy rid iпter ctioп te t D l A - r m Or l r r R 1 k r A 82 D R 1 k m R 1k 2 - 2 RR m R 1 RR 2 -2 4 m r R 1 r m l R 1 1- 2 r l r 2 2 r r 4- Or l r l l A 42 r l l 2 1 - r l r r l m 4- - D 48 4 -8 r rm 2 2- R 1k 2 2- R 1 RR r 2 2- R - - 48 l l l r r l r r A m r l r m l r r D 48 D A l 1 4O24 r 22 r 2 D A l r r m i i l l R r r r R 1 l R 1 l 4- r l 2 2 m k r m D A r m 1 4O 141 D A r m 18 D 48 4 -8 D 48 8 - r l r m l R r m rr l l m - r r r m r - A A A A - - A A AA A - r r r m r l r l - A A A A AA A - r m r R r r l 2 2 4- - r m l rm r D 48 l r R 1 r r 14 R A r r r r r r rm R 1k D 48 4 -8 D 48 8 14 R 118- r 2 A - A l 2 2 l 4- 2 2 A r r rr r rm rr r R R 1 r r r rm r r R 1 r D roteiп e pre ioп пd iпity puri ic tioп r 4- - D 48 4 - D A l r l l r m l - r r m l r A 2 D A r m D 48 4 -8 m l R r m rr 4- l m 4- r r m r r r r r r m r - A A A A - r r r m r -A A A A A A - R r m r rr - l- 2 r m D 48 4 -8 D 48 8 -8 r l r 2 2 4- r l l r 4-1 A r m r m -41- D 48 4 -8 r rr l- 2 r l r l- D 48 4 -8 A D A r m 18 D 48 8 -8 m l R r m l l m - r r r m r -A A A A A A - r r r m r l r R r m i r rr l- 2 - R 1k r r l 2 1 All l m r r r rm i 21 r r r r r - r 1 m r l -D- l r r r l l l r 4 ll m r r r rm - r r l r m 1 m r l m r 8 1 m l r r - r m r r l l m l r l l ll m r r r - r r l r m r 1 m m l l m r 2 m r - l 2 m l 1 m DA 1 m D All r r l m r 4 r m D 1 m DA r r r r r rm r r m r - -R A r hop horyl tioп y r r l D 48 4 -8 D 48 8 - r r - R 1k r 4 m r l r 2 m r 1 m l r 1 m l2 l l A 1 - 2 A l l m r D -A m l r r m 1 r r r 1 D -A l m r ll l r l l A r r l r m r m Q r r m l l r D m R 1k - r l - D 48 4 -8 r A - R 1k roductioп o ST SE K1 iп e пti odie - R 1k r r mm r r r - R 1k r r m r r m r r l r r m r mm l r l r r - R 1k r m 1:1 l r r l iпdiпg tudie - D 48 4 -8 - D 48 8 -8 r r i i rm r R 1 k m r l - r l R 1k - R 1k r l 1 A l l m r r : 2 m r 1 m l m l2 1 m D 1 m DA 1 r -1 r m - r m l r r r 4 1 R 1k l l m mm l r m l R 1 r D r r m 1 m r r r m r m D -A m l r 1 r m r r r 12 D -A r rr r ll l m m r l r ll ll r l - R 1k r m r r l r l lk l - m r I uпoprecipit tioп o CDC r r r r m i i i ll rr 2 2 r r r m m l 1 l r l m A 1 r -1 r r 1m 1 r 1 /m l r m DA 1 m r - mm r 2 R 1 1 r 14 r m r r r A l r r 4 r 1 -2 r mm - m l r l r m r r - 1 l m m l r m r r 1 1 l ll l l r m r 1 r 1 mm r r r l r m r m l r 1 r m r r r 12 D -A l r l D R r l 2 2 l r r l r rm r r r - m Am r m r r e ult SE K1 iпter ct ith CDC48 iп ye t A A r - r m r r k m R 1 R 1k 2 - 2 O R 1- r r D 48A r A 84 i i m r D 48 rm :

r A 2 A 4 A D 48A l A 8A24 r m m D 48A r 8 r r m l l r m 8 kD m m r AAA-A m l A r ll l r AAA- m 2 -414 481- 1 l r l 1 r r r 22 m A- - r l r l l - rm l D 48 4 -8 D 48 44-8 r D 48A r l r l l r 18 r 22 1 4O r 2 - rm l 2 D 48 4 -8 42 D 48 8 - r D 48 r l r rm r R r D 48 4 -8 r r r m m r r ll l r RR m R 1 R 1 RR 2 -2 R 1k m l 1 r - r r r rm ll D 48 r k m R 1 r m m r r R 1 RR T le 1: r D 48 k m R 1 rm D 48 8 -8 18 D 48 4 -8 1 4O24 - r m r rm R 1 r r r 2 2 = r AD 4- = r r D m r r r R - r l r r r /- r r - r = rm D- D- AD- D- AD D 48 D 48 D 48 D 48 D 4 -8 4 -8 4 -8 8 -8 8 - R 1k R 1 RR - - - - m - - - - R 1 r D rm r r R 1 D D 48 4 -8 D 48 8 -8 r r i i r R 1 k m R 1k r - rm l r l - - r r i r r m r l r k rm m m r l r D 48 4 -8 D 48 8 -8 - rm l r m l r - D 48 4 -8 - D 48 8 -8 r r i r r m r m l r - R 1k m l r mm l D 48 r l D Figure 1 i r D 48 k m R - R 1k mm l - D 48 4 -8 r D 48 8 -8 r r r ll l j D -A r l - R 1k r m r m r R 1k l L пe 1 D 48 4 -8 L пe :

- r l - R 1k D 48 4 -8 L пe :

- r l - R 1k D 48 4 -8 L пe 4 5 R 1k 1 L пe 6 D 48 8 -8 L пe :

- r l - R 1k D 48 8 -8 L пe 8: r l - R 1k D 48 8 - r r r rm r l r - r l R 1k r r l j D - r l - R 1k r m r 1 Al r l l D 48 4 -8 r - r l - R 1k 1 l l l l 1 l 1 r l R 1 D 48 4 -8 - R 1k l rl r 1 l - D 48 8 r 1 l r - r l 1 l r l - R 1k 1 l r l R 1k r r r D 48 8 4 - R 1k r m r l l D 48 k m R 1 i i Al r l R 1 r r i i l r r r R 1 - rm l m D 48 r l SE K1 iп e i le to tr п pho phoryl te CDC R 1k l r r l r i i l 2 r r r l r rm r r r R 1 D 48 D 48 4 -8 D 48 8 -8 r r r l r ll R r r l D 48 - - r r r - R 1k r l ll A - m r 2 R 1 l r r l - - Figure : r r l R 1k D - r r r m D A 18 A r l r r l r m r ll - l C r l l A r r l r m r B D B L пe 1:

- R 1k - D 48 4 -8 L пe :

- D 48 4 -8 L пe :

- R 1k D 48 4 -8 C D: L пe 1:

- R 1k - D 48 8 -8 L пe :

R 1k - D 48 8 -8 r r l D 48 4 - r l r E r F r L пe 1:

- R 1k L пe :

- D 48 4 -8 L пe :

- R 1k D 48 4 - R 1 r D r D 48 4 -8 2 l 1 r r l l r r D 48 8 - m l 2 R 1k r r l r r 2 D 48 r l R 1k 2 l rm r D 48 r r l R r r r r r D 48 4 -8 r i i r l - R 1k l r 2 r 2 A r r r l 2 :// k/ r / r r r r l - rm l m D 48 O r m i i D 48 m l r D 48A R 1 l r l D 48 4 -8 D 48 8 -8 r l R 1 r l D 48 l r r rm l 2 m CDC48 пd SE K1 re e er o proteiп co ple D 48 k m R 1 l 14- - r 14 r R A r k r AA 1 4 r 2 k - r A l 2 2 ll l 14 - rm l r R A r R r l R 1 r r r m - r r r r 2 r R 1 R 118- r r 14 r i i i i r r r l - mm r R 1 14- - r r m i i l r r A rm ll ll r R 1 k m l r l r l R 1 l r r l k l 2 2 - r r A R 1 k r m - A i r l R 1 l 14 R A r r r l rm r R 1 m l R 1 r D r m r R 1 r r r rm r - r r R 1k D 48 4 -8 14 R 118- A - A l 2 2 l 4- 2 2 r l ll r l r r r - A A 14 A D A- r 2 2 A mm r l 2 D 48 r r l R 1 l l 14 A l R 1 r k r m A l 2 2 D 48 l r m l A r D 48 m m r i i l r D 48 Al R r k m R r l l r r r r r R D 48 R A r r l r m r l r r m l rm l R 1 D 14 A T le : r r R 1k D 48 4 -8 14 R 118- A - A l 2 2 D / r 4- AD - r m r r r /- r r - r = rm AD- AD- AD- R 1k D 48 4 -8 R 118- D- D 48 4 -8 /- D- 14 - D-R 118- /- - D- A /- D- - A - - CDC48 iпter ct ith SE K1 пd 14 proteiп r r D 48 R D 48 14 r i i ll l r r m - l r i i ll rr 2 2 r rm r mm r R 1- 1 r r m 14 14 r m r m l 14 r r r l l r 14 r D 48 l r i i ll rm r l D r m l 1 D 48 r r m l l r kD rr r l rm m l l r D 48 R r l 2 2 R 1 mm r kD r - r r D 48 r m l 2 14 r m Figure i r D 48 R 1 D 48 14- r L пe 1: D r r l D 48 r r l r m l r i i ll r D 48 r r mm r mm l R 1 1 r 14 r m r r mm - m l r ll j D -A r l D 48 r m L пe : mm r R 1 L пe : mm r 14 r m L пe 4: D r r l R 1 1 r r l r m l r i i ll r R 1 r L пe 5: mm r R 1 R 1 r l R 1 r D mm r m kD r r D - r l r R 1 mm - m l rm r l m l 1 l -m r m l l r r l kD rr r r -r r mm r r - k D r 1 l k r r m r l l i i D 48 l r R 1 l m m r i i 14- - r m l Di cu ioп D 48 R 1 r r r r r rm r D 48 R 1 i i r r l - D 48 r r ll r l R 1 R 1 l r r l D 48 l r r - rm l 2 m r r r R 1 r r R 1k D 48 l 14 A D 48 l r R 1 14- - r i i ll r D 48 r R 1 14 A r m l CDC48 uпctioп D 48 r ll r l r l 1 i i i ll l r l m l m 48 m i 1 m rr l r ll l m r l r rr l r l m r m l l l r l l 1 1 r l l m r l m A r A 1 8 m l m mm l D 48 rm r r l m m r r m l l m r l m i i r r r r l 2 2 R l 2 2 k 48 / l l r r l r r - r l r r m R r r m l 1/ l4 r l 2 m 4 r / r l 2 48/ / r r ll l r r r r mm l r m A- r l / l 48/ / l k l CDC48 e pre ioп p tterп пd co loc li tioп ith SE K i i i i r r m D 48 l r r l r ll r l r l l r l r r l r ll l r l 1 mR A r r l l l m r r -r l m r ll l r r l l r m m l r l l D 48 r l rr mR A r l r l 1 A ll l r l l D 48 r l l l i i ll l m ll r r r r ll R r l 2 2 D r r D 48 l l r l D 48 l l m m r r r AR O 1 r r R r l 2 2 O ll l l m r r r l 1 1 l l l r k R r l 2 2 D r r l m r ll m l r ll l r ll l l l k l 1 A l D 48 -l l r 1 R r l 2 2 D 48 l -l l r O r l r l m r r l m r r D 48 l -l l m l- m rk r r AR 21 R r l 2 R 1 r D R 1 r r m l m l m r rl m r l l r l 2 1 D 48 r r r rl R 1 r r R r m m r r r r l l l m m m r l 2 1 D 48 l m ll m m r R r l 2 2 l r l l ll R 1 A r l l l m m m r r l r r l r r r - r R 1 A m r r ll l r l m l r rl m l 2 2 R 1 A l ll r r ll l r l A r r r R 1 D 48 l l l m r r r R 1 D 48 l r R 1 r l m r r R 1 l D 48 l l ho phoryl tioп regul te huttliпg o Cdc48 p9 C 48 l r ll l r r r m l l l l l r r r l l 1 1 r m R m m r r l 1 l l m l ll l - m r r l r l r r - rm l DDD r l r - rm l l r l l l l 1 8 D 48 r l l ll l i i 48 r l r l 1 k - rm l r D 48 l r l l l R R D D r l - m AAA-m l AAA-A r m r A r l 2 -414 481- 1 D 48 l k m m r r - rm r l r DDDD l r l R 1 r l r r D 48 - rm l 2 m r m mm l D 48 m l / r r r l r ll r r r l 1 r l r l l r m R r m l 2 Al R 1 r l r r DDDD D 48 2 r l r r rm m m r l r l r r DDD r - m l r r D r l r l ll l r r l l SE K1 y uпctioп iп proteiп co ple coпt iпiпg CDC48, F14 пd K r r - mm r R r r r R 1k D 48 l r 14 A m mm l D 48 m l / r l r r k A -2 l r l r 1 l 1 r l - rm l r r r8 r r r r r r 1 r l - 1 ll r r l ll r l l 1 k A -2 R 1 r l D A l 1 A m R 1 r l D m mm l 2 - 1 14- - r m r r r l 1 l 1 r 1 14- - r l m l m 1 r l 14- - R R D A r l r m l 14- - m l rr 14- - m R r r m r l m k l 2 2 14- - R l l m m A r l r m R 1 r D A m r r r A R 1 l 2 2 r r A m l l 14- - r R 1 14 l r l 14 r D l l r 14 r 14- - r i i ll A 14- - m ARQ A rr 14- - m D 48 r l AAA-m l l r l 1 r ll r i i D 48 m l m m r 48 r l 14- - rm r r l r r r r R 1 r R 1 r D 48 14 A r m l m l r m mm l m l / 1 14- - m l R 1 m l l r l A -2 k r l D 48 A l r l / A -2 r l D 48 R 1 m ll- l i i ll D 48 r m l R r l 2 2 r l D 48 R 1 m r l l D r l D r l R 1 D 48 A m r ll r r r r l r R 1 l m r ll ll l c пo ledge eпt l l k k r k k rk r m r m m r r - r k l r D 48 rk r r 8 18 2 r m rl Or r R r O r e ereпce Х Egertoп, M, he, O, Cheп, D, Dru er, B, Burge, W H пd S el oп, L E m mm l m l 48 r r l r ll r r 11 Х Feiler, H S, De pez, T, S пtoпi,, Kroпeп erger,, C oche, M пd Tr, r l i i i l m l l r ll 1 Х Fr hlich, K, Frie, H W, diger, M, Erd пп,, Bot teiп, D пd Mec e, D ll l r D 48 ll-l m l m mm l r m m r r m l l r r m rm r i 11 1 Х ol i,, Lup, N, Koret e, K K, B u ei ter, W пd eter, j r l 48/ m l A: r l r l i 1 1 Х Hecht,, ielle C lz d,, H rtog, M, Sch idt, E D L, Boutillier, K, ro пi l u, пd de rie, S C i i 1 r l l m r m r m l r i 1 1 Х ro ch, E, T i, C, ol eiп, C, Bord llo,, Fiпley, D, Wol, D H пd So er, T r l r m R r r l AAA-A i 1 Х L tterich, M, Fr hlich, K пd Sche п, m r ll l :

48 r R m m r Х L u er, M H, W izeпegger, I, Steiп пп, T, Sch rz, H, M yer,, H пg, I, Lu o itz, W пd rgeп, i i O r k - i 1 1 1 Х L voie, C, Chevet, E, oy, L, Toп, N K, F zel,, o пer, B I, ie eпt, пd Bergeroп, M r r l r l r l l m r l m m l i i i 1 Х Lu o itz, W, M yer, пd rgeп k i i m r l -r l O r 1 1 R 1 r D Х M deo, F, Schl uer,, i ch, H, Mec e, D пd Fr hlich, K r r l r l ll l - l r l l 48 i 1 1 1 1 Х Meпge, M пd Murr y, H r i i l r r l ll- l Х Meyer, H H, Shorter,, See пп,, ppiп, D пd W rreп, A m l m mm l 1 4 l k AAA-A l r r r 1 1 1 Х cheur, E I, M riп, I, M ier O, B o y,, uy ch ert, M пd Hoe tr, D l m l r / 4 -m l m m r i 1 Х iпovich, E, Kere,, Fr hlich, K, Di пt, N пd B r Nuп, S AAA-A / 48 l r r r r l m r l m- r r i Х пcour, D M, Dic ey, C E, r, S пd Bedп re, S Y r r D r m l l m m r m m l ll l i 1 1 1 Х Sehп e, C, DeLille, M пd Ferl, mm l r : r l 14- - r m l l- r r Х Sh h, K, dell r, T W, v п Erp, H, Hecht пd de rie, S C ll l r l l l m r i i i m m r r r k 1 r i 1 Х Sh h, K, u iпov, E, dell r, T W, Wille e, пd de rie, S C i i k - r r l r l m m r r r k 1 1 1 Х Sh h, K, ervoort, пd de rie, S C R l r R l - r r l i 1 1 Х h пg, S H, Ko y hi, r ve,, i пic Wor, H пd Toп, N K r r l 4 1-r l r - r 1 14- - r i 1 Х h пg, S H, Liu,, Ko y hi, пd Toп, N K ll l r l r / D 48 r 4 1-r l r - r 1 i 1 1 1 Ch pter 14 iпdiпg equeпce iп proteiп iп e Iпgrid M ieпtie пd S cco C de rie m r l r tr ct A r r l r l k 14- - r l r k r r m r r r 14- - r r r m l l m r l r l rm R r l r r-l k k R 14- - r 14 k m R 1 r m l 14- - m l l D A l k m ll i i i m m r r r-l k k r r-l k l m k r l m r k 14- - r k m r r r r l l D l r 14- - r r-l k k r l r i i k l 14- - l 14- - Iпtroductioп r r k r l r ll l r ll ll ll ll r ll R r k r l r l ll l r r l r r k r ll l r m r m m r m r ll l r l k m i i m l r m r r r r l r r k r r r m r A 2 r r r rr r r-l k k R l m r k r r m 2 m r rr kD r l r r r l k rm k l r m l ll r m r / r r k k m m r l l 1 8 m ll r - rm l l m r - 1- - l ll l l r r - rm l l r m l l l A l l l l r l r 1 2 - l l l -r m m r r r A A r ll l l l r r l rm r r r 2 r l r A- l l - A m l r l i i R l k r 2 1 k ll l k k r / r k A l l k r l r r r m mm r Am r r m r l rm r ll l m k m l l r m r l m l k ll r r-l k l m k R l k r 2 1 l R r m m r m l l k r r r r r r r r m l r k m l m l r r ll l r m A l r m l m l R r l -r r RR r m m r r r r RR m l l m r - r r r r m r r l r r l l D r 1 O r r k r l r r l r r r r r r m m r l r r k r l m m l O m m l r r l r r k 2 r m m l m r - r r 14 - r r r l m l l m r r r - r r r r r l r ll r r m R r r m r r k l 2 2 r m 14- - r r l r m m m r r r r l r r r A k 2 R 1 r 14- - r 14 r k m R 1 14- - rr r- R Q l l k m l l k l 2 2 r l 4 ll i i r 14- - r r rm m r k 14- - r k m r r r r r l 14- - r rm r ll i i r k r rm l Method Moti e rch k l 2 2 r m R 14- - l 14- - r r r m l i i rm R r A R :// i i r / - / m / - m l ll k r i i r m 14- - r m r r r r m m l l l m 1 R R r l k r 2 1 A r r r m R r rm r r m r r r l l r l O r O i i m 1 r k l r r r R 1 l m 8 m r 2 r r R m r l r k l m r 11 r k A m r 1 r m RO :// r / r / r k m l m :// r k/ r / m/ r k m l r D m D 1 :// r l r r/ r m/2 2 1/ ml/ m m r l 1 i i r k m r m r l 1 14- - m m r r k rr 14- - m r m r l 1 R R m r m l r k r R r R r l r l m l l l m R R k m r l k r 2 1 l l r m l 1 A m r r rm l l l D r r l RO rm l k m r 14- - l l D r l 14- - k m r k r l 21 R R k m 14- - l l D Occurreпce requeпcie R l m rr r r l l r r m m r O l l r l rr r i i r r A A l A1 m l l R 2 - - 2 r k 1 R R l k r 2 1 rr r r m l 14- - r m R r R l l rm l 1/ 2 R r l r r r l m rr r ro ile e rch m l l l m l l D r j l 21 R R 14 - r m l l r l m m ll rr r r r l m 14- - l m r rk l r l 1 8 k :// mm r l / A r l r D- l r l r rm 1 R R r k m l i i r r r A A l A e ult i i m 2 4 8 r r k r r l k l 2 2 r ll r m r m R R 2 rr r m O k l 2 2 r 4 ll i i r r l 14- - r r rm r 1 rr r m r r r m r 14- - rr 1 2 4 8 r r i i m A r r r 1 r 4 l 14- - r r 1 r m r 14- - m m m 1 r m r 14- - r r 1 O r r m r m r m r 2 r r k r r 14- - m m r r rr r l 1 r l r r m r k r r Ar l i i r i i k m R R r rr r r m l m R r r 1 8 r r i i r m m r r r m l m R A m m r R r r r m l m r r r T le 1 O r r m r r k r r l i i r i i r k m R R el tive requeпcy iп el tive requeпcy iп el tive requeпcy iп iпo cid eu ryote proteiп iп e do iп Al A 12 2 2 1 18 A D 22 4 l 414 428 l 8 2 22 l 2 4 18 48 2 24 A 44 44 r 1 4 8 l Q 41 4 Ar R 1 r 8 r 4 1 l r 12 12 r 1 28 r i i m A 2 rr r l 11 2 m ll m r i i m r m r m l m R 11 1 m m r r i i R r l 1 l r r m m r m m r r l r m l l l m 14- - r 4 ll i i r r l 14- - r k l 2 2 l l O r r l r r r rr 14- - r r r m l r r R 1 14 l k r 2 1 m m l l l m k m 1 r r-l k k R r r-l k l m k R m r m r l i i R R m r l 14- - 2 1 1 R R 14- - r R R 14- - r l m l r r r r r m l l r l ll l r 14- - k m R 1 r r ll l r r r r m 14 r ll l r m R 1 r r r l l k k m r r rr 14- - O 2 1 r k l 1 14- - r k m A r - m l m l R 1 k m m r l 1 l 2 1 m l k m l r r r 21 r l 1 4 A r m l 14- - R 1 r l r m k m m l r l r r l 14- - Figure 1 m l m l k m R 1 m - l k m m l r r r m l l 2 1 14- - m l l r m k l k 14- - m 14- - rl l l r r k l 1 88 k r 1 l 1 l m k m R 1 l r r m l r - m l m l R l m 1 R R l R 1 rm l 4 14- - 1 R R k m m r R 1 r - m l m l l A r l m l 14- - l l l Al l 1 k m r l r r l 14- - r T le r m r rr 14- - m R 1 r k 4 14- - l l l m k m l k r 2 1 m r m l - m l k m R ouпt Loop et eeп helice Co eпt 21 14- - l R D - A l - - - - 1 k m A r l 14- - l l D 21 4 l l r r 14 l R 1 All l 14- - r r l ll r 14- - l l l D 14- - m ll - rm l l k m 1 R R 41 r R m l r r ll l r m l k r 2 1 A R 1 21 41 R 2 r ll l r m l -r r RR O 21 r k 14- - l D 12 r R l r ll l r m RR r m l r r r r r 14- - RR-R r r r 14- - m RR-R R 1 RR-R ll m m 14- - T le R R rr 14- - m R r k m l r r l k r 2 1 T le :

r 14- - l l D cce ioп Su ily 14 roteiп п e пu er iпdiпg equeпce A 8 R RR i i i r/ r r k -l k A 2 4 R R A i i i r k A 1 1 R R i i i r/ r r k A 281 R AD D i i i r k A 8 R i i i r/ r- r k -l k A 1 18 RR R Q R A 4 4 RR R Q R A 4 2 RR i i i r r l k k m l m A 1 11 R i i i r/ r r k l A 8 R 1 1 RD A D i i i r r-l k r k A R 1 1 RD D i i i r r-l k r k A 2 2 RR R i i i r r-l k r k A 28 RR R i i i r r l k r k A 28 4 RR R i i i k r A 1 - i i i r r l k r k A 4212 - D i i i r r l k -l k r A 2 24 R R i i i r k i i i r r r A 2 1 R R r A 12 R RR i i i r r-l k k A 2 4 1 R D i i i r k A 2 44 R R i i i r k r T le : r 14- - l r k m cce ioп Su ily iпdiпg roteiп п e пu er equeпce A 2 28 4 R Q R i i l r k A R RD R i i l r i i l r/ r r k A 1 R k i i l RR r r l k r A 4 RR R Q k A 2 2 8 RR R Q i i l RR r r r k A 4 4 A i i l r/ r r k A 4 11 A RDD i i l r/ r- r k l k A 1 8 4 R i i l r k i i l l r r A 1 4 R R R m rk mm A 1 R R r A 21 R D i i l r k A 2 RR D R i i l R r-l k r k A 2 422 RR R A i i l r r l k r k A 1 1 RR D i i l r r l k r k A 8 8 RR D R i i l r k A 1 RR R R i i l r r l k r k A RR R i i l r r r k l k r A 4 RR R i i l r r r k A 1 RR RD A i i l r r l k r k A 2 2 RR i i l r r l k r k A 1 14 RR -2 R i i l r r l k r k A 1 - R R i i l r r l k r k A 1 - R i i l r r l k r k A 1 4 - A R i i l r r l k r k A 2 2 22 - R R i i l r k A 1 R A i i l r k A 2 1 2 A i i l RR r r r k A 1 4 R i i l r k 14- - A 2 R RA i i l r k A 1 84 RR -1 R i i l r r r k A 8 R 1 1 R Q i i l R r-l k r k A R 1 1 R Q i i l R r-l k r k A 28 RR R A i i l r r l k r k l m r k r r m 2 m r m r m l i i r m r l rr r m r 1 r k r l rr r r k m rr m R 1 r r m m r l r k m l 1 R R l 1 14- - m 14- - r k l r m r r l m r r k m T le 4 r m rr 14- - m R r r m l l r l m rr r l roteiп et E pected O erved 2 4 8 i i r 11 1 1 R R 2 8 2 1 R / R k m 8 k m 4 D- 4 21 r k 14- - l l D 1 r k k m r l l 2 O r l r l m r l m r k r rr 14- - m R r 1 m r m l 4 l r m l k R r R r 2 m r l l D r m r r l r r k m l k m r l r m R 14- - k m r l r l r m l l l r r 14 k m R 1 r r r 14- - l D l l ll r l R R r r m 14- - m r l l l D r j l m l l l m 21 R R 14- - l 2 r j l l k l r l l l r l r l 1 R R r r ll m k r l l r r m r r k 14- - l l D A r l k r r r m l l D l m r r l r m l r i i m r m l r l l l D l r k 14- - r A r r r k 14- - l l D m r k i i i i r m 1 r k r r r R 1 r r r r k l m r r k A m r r r k m l m r D m O 1 r 4 rr 14- - m 1 4 8 r r R r R m l 1 r k r 14- - Figure l l l m r l l D r j l 21 r k All 14- - l l r l m l l l m R R k m r l k r 2 1 A r r m R r l l l D r l r 1 r m 14- - l r r r k rm l 14- - k m r m 12 r l k m 21 R R k m 14- - l l D 14- - l l D r r l 1 l r k 14- - l D- l r l r l r T le 5 A l r k rr 14- - m R cce ioп 14 iпdiпg roteiп п e пu er equeпce A 1 2 DR r A 1 14 l r A 1 4 R r m A 41 R r A 2 8 2 R l - k 1 A 48 A l - k A A 2 R r k A 2 4 r k A 1-r l r k A R R r k 1-l k r Di cu ioп k m R 1 14- - R Q l l l D r rm r r 14- - m R k m 1 R R 21 r k 14- - l l D m r r m 1 m l Am r k i i r R r R r r r 14- - m l r r 14- - m R i i r m k l 2 2 r l 4 ll i i r 14- - D r m R m l rr m rm ll l r rr m r m r r l l rr 14- - m l l r r r r rr 14- - r r r m l r r R 1 14 r r r r r k m r r l l 14- - r l l r k m R R r m 14- - l D m r l r l r m l r R 1 14 r 14 R 1 k m l l r r 14- - l D l l ll r l R R r m l 14- - l l l l r l r l l r r m l ll r r r 14- - r A 14- - m r r r m m k r R r R 14- - l l D r r l m r l l D r l m k r l r r l l r r l r m 1 rm r m r r rm r r r l k - l r r r l l D m r l l r l r l l 14- - r l m r m l m l 1 k 14- - r r r l m m l l m l l D l l l m l l l r r r l r l l D r j l r l l m r k 14- - l m 14- - m l r l r l r m r r m ll 14- - r r m r 14- - k m m R r m 14- - r r l r m m m r r r r l r r r A k 2 2 r r l m r 14- - r k m ll r m r rm r m m R r m l l l m m m r -A r -r 14- - r - rm r l -O m l 2 1 r - rm 1 i i r k 14- - r r m l m R l m r l i i r l rm r m r l 1 r l r r rm r m 14- - r l 1 l 1 m l l 14- - m r r ll l - l r r l - r r - rm l m rm m r r l r l - rm l m rm l m m r r l mm r r l r m r r l 1 14- - m r l r r r l k R 1 R 14- - l l D A 1 l R r R 1 r r k m 2 2 R 1 14 - m k m R 1 r A 14- - r l 2 2 14- - r r r r r m r R A 1 l 2 R 1 l m m r l ll 14- - r 14- - r r r r R 1 m m r l m l r l l l D l k m l l r r r l l r r l r 14- - r m l r r l rm 14- - R 1 r r l r r r r A 14- - r rm m r r r l 14- - m r R 1 m r r 14- - m r m r/ l r r r r r R 1 r k r r r - r l m r r r R - r k r 14- - m r l l r r ll m m l r l r r k 14- - m l l D l 2 m r R 1 Am r r r m l m m r R r l r m r m l k m k l r r r r r m i l 1 r r R m l m m r m r l k l m l - k -l k r m m r m l l k r 2 1 l 14- - Am r k 14- - r R r R l l r A 1 14 r m r A 41 A 1-l k r l A r l l : :// l / l / m l / l 2 18 ml r r m l m m r l - r k 1 A r l l r l ll l k m l 2 2 r r l k l - k r 2-l k k 1-r l r k r l k 14- - m l ll R 1 r l r l m r rm l 2 1 r l D 48 r r l ll R r l 2 l r R 1 ll r 4 r r 14- - r m l k R 1 ll ll l r l l l rl r r r m r l rm r r j rm l r m r l r l r r R 1 14- - m r rm r r m l r r l l R c пo ledge eпt l l k k r r r k r m l r l mm m r l l l k k - r j r l - r e ereпce Х it eп, l 14- - rm r r m r rm r l r m m l m mm l rm r i 1 1 Х eпo e Iпiti tive A l m l r l i i i Х ruqu, D пd Michel, C A r i 1 Х Bur c, W пd Sh, S l r : l i i 1 11 Х Eddy, S r l rk m l i i i 1 Х Furl пetto, W, Dey, B, Lop czyп i, W пd Ni ley, S 14- - r r l r r r r l r r i Х H п, S K пd Huпter, T k r r k r m l : k l m r r l Х H п, S K uiпп, M пd Huпter, T r k m l : r r l l m i 1 Х Hecht,, ielle C lz d,, H rtog, M, Sch idt, E D L, Boutillier, K, ro пi l u, пd de rie, S C i i 1 r l l m r m r m l r i 1 1 14- - Х v п der Hoeveп, C, v п der W l, C M, uur,, v п Di, M C M пd v п Blitter i, W 14- - l l r k - R -1:

r l 14- - r l i Х Hu rd, S, Wei, L, Elli, L пd Heпdric oп, W r l r r r k m m l r r Х Hu e, M пd Kuriy п, rm l l r k Х elich Ott пп, C, Weiler, E W пd Oec iпg, C r l r 14- - r rm l l m m m r -A l r r r i Х ohп oп, L N, Lo e, E D, No le, E M пd O eп, D r r l r r r r l r k 1 11 Х Ko e, B пd Die eпho er, l -r r : r l m i i 1 1 1 Х Li,, Weп,, Le e, K, Do e, T, T, F E пd W l er, C A i i RR r r-l k r k r R 1 m l r r ll 11 Х Liu, D, Bieп o,, eto, C, Collier,, H l п, F пd Liddiпgtoп, r l r r rm 14- - r 1 1 1 Х Miпor r, D L пd Ki, S - r r r rm r Х N, K H пd Li, R 1/ A 1 r r k r m r r ll Х Ni hih,, Soy пo, T, I hi, M, r i, S, T п, H, d, T, Irie, K, Ito, M, Ter d, M, B ппo, H, Y z i, Y пd M chid, Y ll l l k r r k -l k r / A m l Х пcour, D M, Dic ey, C E, r, S пd Bedп re, S Y r r D r m l l m m r m m l ll l i 1 1 1 Х o eпqui t, M, Sehп e,, Ferl,, So riп, M пd L r oп, C l 14- - r m l : l r m r rm m l ll l r r m r l l Х Sehп e, C, DeLille, M пd Ferl, mm l r : r l 14- - r m l l- r r r Х Sh h, K, ervoort, пd de rie, S C R l r R l - r - r l i 1 1 Х Shiu, S H пd Bleec er, B R r-l k k r m i i rm m l m l r l m l r r k i 1 1 Х Shiu, S H пd Bleec er, B l r r-l k k m l : r ll i i i Х T пg, X, Frederic, D, hou,, H lter п, D, i, Y пd M rtiп, B l r l r A r k i Х Tho p oп, D, i oп, T, le пi, F, e п ougiп, F пd Higgiп, D A - r : l l r r m l l l m l l l i i Х Wu, K, Lu,, Sehп e, пd Ferl, r l r m l 14- - r r r m r r m r i i Х Xi o, B, S erdoп, S, oпe, D H, Dod oп,, Soпei, Y, it eп, пd liп, S r r 14- - r m l r r m l l ll 1 1 1 Х Y e, M B, ithiпger, K, oliпi, S, C roп,, it eп,, Le er, H, liп, S, S erdoп, S пd C пtley, L C r r l r 14- - 1 1 1 Ch pter Su ri iпg di cu ioп r r k r l r ll l r ll ll r ll r r ll R r-l k r k R r ll l r m r m m r m r ll l r l k m r r ll l r m l r l m r l r l r r ll r l r m r r - r m r m l r l r l r l m l r rr m D- rm r l r r l l r l r - r r l r r r - r r l l r r l r l r r k m l r l m l l r i i m m r R r-l k 1 R R l r l -r r RR l r m m r m l r - r k l 2 l 2 1 R 1 r l r m r r rl m r l r l l l 2 r R 1 r m m r rm l r r r l m m r rm R 1 r r l r l l m r l m l 2 j r r r r r k m R 1 m l l r m R 1 r r O r l r m m r l r r - r r r r k l 2 r r m r r r r k m R 1 A r l r r R 1 r r r r r 14- - r 14 AAA-A D 48 R A r R m r r r A1 r 1 r m -l k r O r r R 1 r r l l 14 D 48 R D m l l r R A r mm r r R R 1 r r l D 48 r l r r r l R 1 A1 ll l R 1 r r r l r rm m r r m - r l R 1 r r r r l r m - r r r m l r R r k ll r l r l r l r r r l r l R 1 l 2 2 rm k - r A l r l R 1 i i l r l l ll R 1 A r -l l r m A l R 1 A l l r R 1 r r r D 48 r m r l r A m m R ll A - r r k m r r r r R 1 r l l r k A 1 - rm l m R 1 k m m 2 2 A R 1 l R m l m m r R r A 84 RR-r r k A 1 R 1 i i i i r r l r i i l 2 2 l k l r r r m r m R ll i i r R 1 k m l rm m m r l l 2 1 R 1 r r r r r l R 1 r m m r r m r r r r R A - r r r r r m r l ll R 1k - r r l k r l k r r r - r l l m r l r r r r r r l m m r r k l 2 r r m l m r R 1 k m m r r r 14 r l R k m l k r r r r r l r R 1 14 rm i i ll 14 r r l r l R k m 14 R 1 l r r l 14 i i i i r rm mm r ll l r l l m l l r r l r l l ll R 1 l m m m r r l 14 l 14- - r m l l r 28- 1 kD r r m l m r r l 1 14- - r r r l r r k r l 1 r rm i i R l 2 1 Al 14- - rm r r m l r r l l r l r r r r R l 2 14- - r l r rm r r r l r l l 1 14- - r m r r r r r l r r m m l ll m l l l 1 14- - l ll l r r l r r l k l r l l r r l - r l 2 1 k r m l r 14- - r r l r r - r r r r l r rm R 1 k 14 m r r l r l r r R 1 k m r r l 14- - m r rm 14 r r l R 1 r r l r r 14 l R r l 14- - r - r r l r rr r r / r r r r l 14 l r r m R 1 ll m l r r r l R mm r r R 1 D 48 rm i i l ll - mm r D 48 r r l r l R 1 k m R 1 l r r l D 48 l r r - rm l 2 m r r r R 1 r r R 1k D 48 l 14 A r D 48 14 rm l ll i i D 48 l r r l r r l r ll l r l 1 r D l m ll m m r A ll l r l l D 48 r l l l i i ll m r ll l r l r r R r l 2 2 R 1 A r r rl m l 2 2 r r r R 1 D 48 l r R 1 r l m r r R 1 l D 48 l l 48 m mm l m l r r r ll l r r l k ll l 1 8 m m m r r l 2 2 r r l r r - r l r r m R R l 2 2 r r mm l r m A- r l / l 48/ / l k l 1 48 r l l m l ll l - m r m k l l r ll l r l r l r l r r - rm r l 1 8 m mm l D 48 m l / r l r r k A -2 l r l r 1 l r l r l l r m R r m l 2 r l r r - rm D R 1 m m r l r l r r - rm 48 r - m l r r r r D r ll D 48 l R r l 2 2 r l D 48 R 1 m r l ll l r r l l D 48 r m l A l 1 A m R 1 r l D 48 r ll l r r l l D D 48 l r 14 A l 14- - l 1 A m l 14- - r k 2 r R l m R - m l R 1 14- - m m R k l 2 2 l l l m l l r m r l k m l D 48 A l 14- - r r l r R 1 r r r r l m r ll ll l r r l i i k r l ll l 14- - r ll l r r D 48 l l r r l r r - r l r r m R R l 2 2 r r r r m l r m l r l r m R l r l 1 D 48 l r r r m l r r m r r l k r m l r r l R 1 r r m l r r r ll r m m m r l r l m m r l r r ll r 2 2 R 1 r l - r A r l l 2 2 l m mm l 1 l4 48 r r r l 2 2 k m R 1 m m r r ll m l r D 48 m m r R 1 r r r r r l D 48 R 1 ll m r r m l m l l r r l r l l ll R 1 D 48 l r r r ll mm r e ereпce Х Boпi ciпo, S пd Wei п, M r l r r r i 1 Х Feiler, H S, De pez, T, S пtoпi,, Kroпeп erger,, C oche, M пd Tr, r l i i i l m l l r ll 1 Х ol i,, Lup, N, Koret e, K K, B u ei ter, W пd eter, j r l 48/ m l A: r l r l i 1 1 Х Hecht,, ielle C lz d,, H rtog, M, Sch idt, E D L, Boutillier, K, ro пi l u, пd de rie, S C i i 1 r l l m r m r m l r i 1 1 Х L voie, C, Chevet, E, oy, L, Toп, N K, F zel,, o пer, B I, ie eпt, пd Bergeroп, M r r l r l r l l m r l m m l i i i 1 Х Li,, Weп,, Le e, K, Do e, T, T, F E пd W l er, C A i i RR r r-l k r k r R 1 m l r r ll 11 Х Lopez iroп,, K пoh, пd u ell, l r l 2 r r r D A m k i 11 Х M deo, F, Schl uer,, i ch, H, Mec e, D пd Fr hlich, K r r l r l ll l - l r l l 48 i 1 1 1 1 Х N, K H пd Li, R 1/ A 1 r r k r m r r ll Х cheur, E I, M riп, I, M ier O, B o y,, uy ch ert, M пd Hoe tr, D l m l r / 4 -m l m m r i 1 Х ig glio, E, Dur пd, N пd Meyer, C A r m - rm l m r r r r m rk r l 14- - i 11 1 r Х iпovich, E, Kere,, Fr hlich, K, Di пt, N пd B r Nuп, S AAA-A / 48 l r r r r l m r l m- r r i Х пcour, D M, Dic ey, C E, r, S пd Bedп re, S Y r r D r m l l m m r m m l ll l i 1 1 1 Х o eпqui t, M, l ter ord, M, L r oп, C пd So riп, M D m i i m r l 14- - r m r r l i 1 1 1 Х o eпqui t, M, Sehп e,, Ferl,, So riп, M пd L r oп, C l 14- - r m l : l r m r rm m l ll l r r m r l l Х Schle iпger, ll ll r r r k 1 Х Sehп e, C, DeLille, M пd Ferl, mm l r : r l 14- - r m l l- r r Х Sere rii ii, I, E to,, Ber п, M пd ole i, E A r l - r m i i Х Sh h, K, dell r, T W, v п Erp, H, Hecht пd de rie, S C ll l r l l l m r i i i m m r r r k 1 r i 1 Х Sh h, K, u iпov, E, dell r, T W, Wille e, пd de rie, S C i i k - r r l r l m m r r r k 1 1 1 Х Sh h, K, ervoort, пd de rie, S C R l r R l - r - r l i 1 1 Х Strou, пd eпt, D m r l r r rm r r 1 Х Sveппelid, F, Ol oп,, iotro i, M, o eпqui t, M, Ott п, C, L r oп, C, Oec iпg, C, So riп, M r l r- 48 rm l m m m r -A r r r l r 14- - r 1 Х Wu, K, Lu,, Sehп e, пd Ferl, r l r m l 14- - r r r m r r m r i i mm r Х Meyer, H H, W пg, Y пd W rreп, D r j m mm l r m l 4 1- l4 Х h пg, S H, Ko y hi, r ve,, i пic Wor, H пd Toп, N K r r l 4 1-r l r - r 1 14- - r i 1 Х h пg, S H, Liu,, Ko y hi, пd Toп, N K ll l r l r / D 48 r 4 1-r l r - r 1 i 1 1 1 Su ry R r k r l r l ll l r ll ll r ll m m r R r-l k 1 R 1 r r-l k k R l -r r r ll l r m R 1 r r l r l l m r l m r m m R 1 l r r m l k r r - r m r r r r k m R 1 A r l r r R r r r r r m m r i i i m l 14- - r ll 14 AAA-A D R A r R m r r r A1 r r m -l k r A r l k r r m l l r m R 1 r r k r rm i k rm r R 1 r D 48 R r r l R 1 i i r r l r R 1 r r r l i r r rm rm r R 14 r r l r l R 1 k m r R 1 14 i i m r mm r l ll rr R l r l l ll R 1 14 r k m R 14- - m R Q rr r 4 m l l k m l l R 1 r 2 i i r r-l k k 14- - m l k 14 A D 48 r r l r l k m i i i i r m r mm r R 1 l r r l D 48 r r - rm l 2 r r D 48 l l r R 1- r r r A r D 48 14- - r rm l ll - mm r l m mm l D 48 m l / r l A - k r l 1 14- - r ll l r l l D 48 r R 1 l m r ll ll l r r l i i r k r l ll l 14- - r Ei itteп die п de So ti che E ryogeпe e eceptor Kiп e 1 iпdeп Samenvatting R r k k l l r r r l O m r j r kk j r l l ll l r r l l l l r l D m m r R r R 1 r r k i i r k r j l jk r kk j l r r r r kk l l m r l jk r lk r R 1 j l r D r m m l - r m r r m r ll l r k l r r m m l jk r r D j 14 l i i m l 14- - D 48 A R R A A1 k l m r r 1 rk l l r m - m Om r l R 1 k r l r m r rm k l r R 1 l r r k k r 14 D 48 R k r R 1 r l r r ll r r r l r D r 14 m R 1 r m l i i r m r l k 14 j rk r R 1 l k m r r m l r l D r k l ll D r m l - mm r r m m r k r m l l r r l r l l 14 R 1 k m R 1 r r m l jk 14- - D l r r k m l l l r k l r m R m k 2 r r r k i i D r D 48 m R 1 i i m r m l ll r m l - mm r l 14 D 48 j rk r R 1 l k m r r r l Al D 48 k r R 1 r r l r D r r m r r l m r D 48 r m - r m l ll R 1 m r k D 48 14 A k D l D 48 rl jk ll r r m / k r k A -2 r r l r r 1 r r l r A 1 r l j 14- - r l k l D 48 i i ll j r R 1 r kk j l l r r l l r l k l k i i r j l jk r j l l k m l jk 14- - r D п oord r l j r l jk r:

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