PLK4
Serin/treonin-protein kinaza PLK4, znana i kao pololika kinaza 4 jest enzim koji je kod ljudi kodiran genom PLK4 sa hromosoma 4.[5] Homolog Drosophila je SAK, homolog C. elegans je zyg-1, a homolog kod roda Xenopus je Plx4.[6]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 970 aminokiselina, а molekulska težina 108.972 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MATCIGEKIE | DFKVGNLLGK | GSFAGVYRAE | SIHTGLEVAI | KMIDKKAMYK | ||||
| AGMVQRVQNE | VKIHCQLKHP | SILELYNYFE | DSNYVYLVLE | MCHNGEMNRY | ||||
| LKNRVKPFSE | NEARHFMHQI | ITGMLYLHSH | GILHRDLTLS | NLLLTRNMNI | ||||
| KIADFGLATQ | LKMPHEKHYT | LCGTPNYISP | EIATRSAHGL | ESDVWSLGCM | ||||
| FYTLLIGRPP | FDTDTVKNTL | NKVVLADYEM | PSFLSIEAKD | LIHQLLRRNP | ||||
| ADRLSLSSVL | DHPFMSRNSS | TKSKDLGTVE | DSIDSGHATI | STAITASSST | ||||
| SISGSLFDKR | RLLIGQPLPN | KMTVFPKNKS | STDFSSSGDG | NSFYTQWGNQ | ||||
| ETSNSGRGRV | IQDAEERPHS | RYLRRAYSSD | RSGTSNSQSQ | AKTYTMERCH | ||||
| SAEMLSVSKR | SGGGENEERY | SPTDNNANIF | NFFKEKTSSS | SGSFERPDNN | ||||
| QALSNHLCPG | KTPFPFADPT | PQTETVQQWF | GNLQINAHLR | KTTEYDSISP | ||||
| NRDFQGHPDL | QKDTSKNAWT | DTKVKKNSDA | SDNAHSVKQQ | NTMKYMTALH | ||||
| SKPEIIQQEC | VFGSDPLSEQ | SKTRGMEPPW | GYQNRTLRSI | TSPLVAHRLK | ||||
| PIRQKTKKAV | VSILDSEEVC | VELVKEYASQ | EYVKEVLQIS | SDGNTITIYY | ||||
| PNGGRGFPLA | DRPPSPTDNI | SRYSFDNLPE | KYWRKYQYAS | RFVQLVRSKS | ||||
| PKITYFTRYA | KCILMENSPG | ADFEVWFYDG | VKIHKTEDFI | QVIEKTGKSY | ||||
| TLKSESEVNS | LKEEIKMYMD | HANEGHRICL | ALESIISEEE | RKTRSAPFFP | ||||
| IIIGRKPGST | SSPKALSPPP | SVDSNYPTRE | RASFNRMVMH | SAASPTQAPI | ||||
| LNPSMVTNEG | LGLTTTASGT | DISSNSLKDC | LPKSAQLLKS | VFVKNVGWAT | ||||
| QLTSGAVWVQ | FNDGSQLVVQ | AGVSSISYTS | PNGQTTRYGE | NEKLPDYIKQ | ||||
| KLQCLSSILL | MFSNPTPNFH |
Struktura
urediPLK4 sadrži N-terminalni domen kinaze (ostaci 12-284) i C-terminalni lokalizacijski domen (ostaci 596-898).[8] Ostali pololiki članovi kinaza sadrže po dva C-terminalna polo kutijska domena (PBD). PLK4 sadrži ove dva domena uz treći PBD, koji olakšava oligomerizaciju, ciljanje i promovira transautofosforilaciju, ograničavajući duplikaciju centriola, jednom po ćelijskom ciklusu.[8]
Funkcija
urediPLK4 kodira člana polo porodice serin/treonin protein kinaza. Protein se nalazi na centriolaama — kompleksnim strukturama zasnovanim na mikrotubula makoje se nalaze u centrosomima — i reguliše duplikaciju centriola tokom ćelijskog ciklusa.[5] Prekomjerna ekspresija PLK4 rezultira amplifikacijom centrosoma, a nokdaun PLK4 rezultira gubitkom centrosoma.[9][10]
Kao meta lijeka protiv raka
urediInhibitori enzimske aktivnosti PLK4 imaju potencijal u liječenju raka.[11][12] PLK4 inhibitor R1530 podregulira ekspresiju kinaze mitozne kontrolne tačke BubR1, što zauzvrat dovodi do poliploidije, čineći ćelije raka nestabilnim i osjetljivijim na emoterapiju. Nasuprot tome, normalne ćelije su otporne na efekte R1530 koji izazivaju poliploidiju.[13]
Drugi inhibitor PLK4, CFI-400945, pokazao je efikasnost na životinjskim modelima raka dojke i jajnika.[14][15]
Za još jedan inhibitor PLK4, centrinon, prijavljeno je da iscrpljuje centriole u ljudskim i drugim tipovima ćelija kičmenjaka, što je rezultiralo zaustavljanjem ćelijskog ciklusa ovisnog o p53 u G1-fazi.[16] Inhibicija PLK4 upotrebom hemijske genetičke strategije potvrdila je ovo p53-zavisno zaustavljanje ćelijskog ciklusa u G1-fazi.[17]
PLK4 je također identificiran kao potencijalna terapijska meta za maligne rabdoidne tumore, meduloblastome i moguće, druge embrionske tumore mozga.[18][19][20][21]
Interakcije i supstrati
urediDokumentirane podloge za PLK4 uključuju STIL, GCP6,[22] Hand1,[23][24] Ect2,[25] FBXW5,[26] i samog sebe (putem autofosforilacije). Autofosforilacija PLK4 rezultira ubikvitinacijom i naknadnim uništavanjem proteasoma.[27][28]
Pokazalo se da PLK4 ulazi u interakcije sa stratifinom.[29]
Reference
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025758 - Ensembl, maj 2017
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Dopunska literatura
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