cyclins: a structure and function anna ajduk, hulya cabadak, karolina czaja, heli honkala, stephen...

Cyclins: a structure and

function

Anna Ajduk, Hulya Cabadak, Karolina Czaja, Heli Honkala,

Stephen Huisman

Introduction

Conserved domains and motifs

AAMTPHDFIEHFLSKMPEADENKQTIRKH-------AQTFVALCATDVKFISNPPSMVAA AAVTPHDFIEHILRKLPQQKEKLSLIRKH-------AQTFIALCATDFKFAMYPPSMIAT AAVIAHDFLALILHRLSLPSDRQALVKKH-------AQTFLALCATDYTFAMYPPSMIAT AAPTVNQFLTQYFLHLQPANCKVESLAMF-------LGELSLIDAD--PYLKYLPSLIAG GRPLPLHFLRRAS-KVGEVDVEQHTLAKY-------LMELSMLDYD---MVHFAPSQIAA SPLTIVSWLNVYVQVAYVNDTGEVLMPQYPQQVFVQIAELLDLCVLDVGCFRFPYGVLAA

cyclinD1 1 -----------------------------------------------MEHQLLCCE-VET cyclinD2 1 -------------------------------------------------MELLCCE-VDP cyclinD3 1 -------------------------------------------------MELLCCEGTRH cyclinA 1 KTRRVAPLKDLPINDEHVTAGPSWKAVSKQPAFTIHVDEAEETQKRPAELKETECEDALA cyclinB1 1 PLKREAKTLGTGKGTVKALPKPVEKVPVCEPEVELAEPEPEPELEHVREEKLSPEPILVD cyclinE 1 KIDKTVKSEDS--------SQPWDDNSACVDPCSFIPTPNKEEDNELEYPRTAFQPRKIR

TEETCAPSVSYFKCVQKEIVPSMRKIVATWMLEVCEEQKCEEEVFPLAMNYLDRFLSLEP IEERYLPQCSYFKCVQKDIQPYMRRMVATWMLEVCEEQKCEEEVFPLAMNYLDRFLAGVP LEERYVPRASYFQCVQKEIKPHMRKMLAYWMLEVCEEQRCEEDVFPLAMNYLDRYLSCVP MEVKCKPKVGYMK-RQPDITNSMRAILVDWLVEVGEEYKLQNETLHLAVNYIDRFLSSMS LEEEQSVRPKYLQ--GREVTGNMRAILIDWLIQVQMKFRLLQETMYMTVSIIDRFMQNSC NKEKTYLRDEHFLQRHPLLQARMRAVLLDWLMEVCEVYKLHRETFYLAQDFFDRYMASQQ

GSVVAAMQGLNLGSPN-----------------NFLSCYRTTHFLSRVIKCDPDCLRACQ GSVGAAICGLQQDDEV-----------------NTLTCDALTELLAKITHTDVDCLKACQ GSIGAAVLGLGACS---------------------MSADELTELLAGITGTEVDCLRACQ AAFHLALY--------------------------TVTGQSWPESLAQQTGYTLESLKPCL GAFCLALK--------------------------ILDNGEWTPTLQHYLSYSEDSLLPVM SALYHFSSLELMQKVSGYQWCDIEKCVKWMVPFAMVIREMGSSKLKHFRGVPMEDSHNIQ

-LKKSRLQLLGATCMFVASKMKETIPLTAEKLCIYTDNSIRPEELLQMELLLVNKLKWNL -TPKTHLQLLGAVCMFLASKLKETIPLTAEKLCIYTDNSVKPQELLEWELVVLGKLKWNL -TRKAQLQLLGTVCLLLASKLRETTPLTIEKLCIYTDQAVAPWQLREWEVLVLGKLKWDL -VLRGKLQLVGTAAMLLASKFEEIYPPEVAEFVYITDDTYSKKQVLRMEHLVLKVLAFDL -VPKKMLQLVGVTAMFIASKYEEMYPPEIGDFAFVTNNTYTKHQIRQMEMKILRVLNFSL NIIKTLLQLIGISALFIASKLEEIYPPKLHQFAYVTDGACSGDEILTMELMMMKALKWRL

EQIEALLESSLRQAQQNVDPKATEEE-------------GEVEEEAGLACTPTDVRDVDI EQIEALLLNSLQQFRQEQHNAGSKS-----------------VEDPDQATTPTDVRDVDL EQIEAALRESLREAAQTAPSPVPKAPR------------GSSSQGPSQTSTPTDVTAIHL VDLHQTYLKAPQHAQQSIREKYKHS-----------------KYHSVSLLNPPETLSV-- QHLAKNVVMVNCGLTKHMTVKNKYAAS------------KHAKISTLAQLNCTLVQNLSK THTNSLDLLDKAQAKKAILSEQNRISPPPSVVLTPPPSSKKAEQRAGDRMTKPAIASKDS

------------------------------------------------------------ ------------------------------------------------------------ ------------------------------------------------------------ ------------------------------------------------------------ AVTKA------------------------------------------------------- GVEAAAWSSLCCLGGQEPLQMLCSMERCISSGAAGVCKMPWMEVLLLNARCFNYRVKYTS

------------ ------------ ------------ ------------ ------------ HLQNTTECSRSC

IRRAY--------------------PDTNLLND-RVLRA------------------MLK VRRAV--------------------PDRNLLED-RVLQN------------------LLT APRAG--------------------PDPRLLGDQRVLQS------------------LLR FNAAVSLPAARKPLTPLDYPMDGSFESPHAMDMSIVLEDKPVNVNEVPDYQEDIHTYLRE NPSPSPMETSG---CAPAEEYLCQAFSDVILAVSDVDADDGADPNLCSEYVKDIYAYLRQ PPRASP------------------LPVLNWGNREEVWR-------------------IML

cyclin-boxN C

N-domain(5 helices)

C-domain(5 helices)

R - x(2) - [LIVMSA] - x(2) - [FYWS] - [LIVM] - x(8) - [LIVMFC] - x (4) - [LIVMFYA] - x(2) - [STAGC] - [LIVMFYQ] - x - [LIVMFYC] - [LIVMFY] - D - [RKH] - [LIVMFYW]

Structure of mouse cyclin B1

Cyclins bind with cyclin-depended kinases (CDKs) and activate them:

CycA – CDK 2CycB – CDK1

CycD – CDK 4,5CycE – CDK2

cycCDK

Cyclins bind with CDKs

Crystal structure ofcycA1 and CDK2

Model of cycB1 and CDK1

Cyclins are regulated by phosphorylation

S90 S197

S234 T287cycD1

PKA GSK-3

turnovercontrol

G1/S progression

S126 S128

S133 S147cycB1

PLK

MAPK

nuclear localisation

phosphorylation by Plk

S- and M-phase cyclins contain a destruction box

PAATSKPGLRPRTALGDIGNKVS VTAASKPGLRPRTALGDIGNKVS -VVATKPGLRPRTALGDIGNKA- AAPVQQPRTRAALAVLKSGNPRG LAPAQQPR---AQAVLKAGNVRG

RTALGDIGN

RAALAVLKSGN

Hum-cycB1Mou-cycB1Xen-cycB1Hum-cycA2Mou-cycA2

proteolysis cyc

Phylogenetic comparison

Thank you, Tesekkurler, Dziekujemy,Kiitos, Bedankt

Hulya

Karolina

AnnaHeli

Stephen