PI4K2A
Fosfatidilinozitol 4-kinaza 2-alfa je enzim koji je kod ljudi kodiran genom PI4K2A.[5][6][7]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 479 aminokiselina, а molekulska težina 54.022 Da.[8]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MDETSPLVSP | ERAQPPDYTF | PSGSGAHFPQ | VPGGAVRVAA | AAGSGPSPPG | ||||
| SPGHDRERQP | LLDRARGAAA | QGQTQTVAAQ | AQALAAQAAA | AAHAAQAHRE | ||||
| RNEFPEDPEF | EAVVRQAELA | IERCIFPERI | YQGSSGSYFV | KDPQGRIIAV | ||||
| FKPKNEEPYG | HLNPKWTKWL | QKLCCPCCFG | RDCLVLNQGY | LSEAGASLVD | ||||
| QKLELNIVPR | TKVVYLASET | FNYSAIDRVK | SRGKRLALEK | VPKVGQRFNR | ||||
| IGLPPKVGSF | QLFVEGYKDA | DYWLRRFEAE | PLPENTNRQL | LLQFERLVVL | ||||
| DYIIRNTDRG | NDNWLIKYDC | PMDSSSSRDT | DWVVVKEPVI | KVAAIDNGLA | ||||
| FPLKHPDSWR | AYPFYWAWLP | QAKVPFSQEI | KDLILPKISD | PNFVKDLEED | ||||
| LYELFKKDPG | FDRGQFHKQI | AVMRGQILNL | TQALKDNKSP | LHLVQMPPVI | ||||
| VETARSHQRS | SSESYTQSFQ | SRKPFFSWW |
Klasifikacija
urediOvaj gen kodira fosfatidilinozitol 4-kinazu koja katalizira fosforilaciju fosfatidilinositola na položaju D-4, dajući fosfatidilinositol 4-fosfat (PI4P). Osim činjenice da PI4P služi kao prekursor za druge važne fosfoinozitide, poput fosfatidilinositol 4,5-bisfosfata, PI4P, neophodns je molekula u ćelijskoj signalizaciji i prometu posebno u Golgijevom aparatu i trans Golgijevoj mreži.
Fosfatidilinozitol 4-kinaze evolucijski su konzervirane među eukariotima i uključuju četiri ljudske izoforme
- fosfatidilinositol 4-kinaza alfa (PI4KA)
- fosfatidilinositol 4-kinaza beta (PI4KB)
- Fosfatidilinositol 4-kinaza 2-alfa (PI4K2A)
- fosfatidilinositol 4-kinaza 2-beta (PI4K2B)
Funkcija
urediFosfatidilinositol 4-kinaza 2-alfa (PI4K2A) je najzastupljenija fosfatidilinozitol 4-kinaza u ljudskim ćelijama i odgovorna je za sintezu približno 50% ukupni PI4P unutar ćelije. PI4K2A je uglavnom povezan s membranama trans Golgijeve mreže i ranim i kasnim endosomima;[9] njegova membranska povezanost postiže se teškom palmitoilacijom unutar specifičnog motiva bogatog cisteinom.[10] Osim sinteze fosfatidilinositol 4,5-bisfosfata, PI4K2A je uključen u različite ćelijske procese, uključujući promjenu membrana, regulaciju endosomskog sortiranja, promovirajući regrutovanje ciljnih proteina u endosomima ili trans Golgijevoj mreži ili transdukciju signala. Posebno regulira npr. ciljanje kompleksa klatrinskog adaptera na Golgijev aparat,[11] signalni EGFR signaling,[12] ili Wnt-signalni put.[13]
Klinički značaj
urediDisfunkcija PI4K2A može doprinijeti rastu tumora,[14] spazamskoj paraplegiji,[15] Gaucherovoj,[16] ili Alzhemerovoj bolesti.[17]
Struktura
uredi
PI4K2A se sastoji od prolinom bogate N-terminalne regije i kinaznog domena koji se nalazi C-terminalno. Prolin-bogato N-terminalno područje sadrži fiziološki važna mjesta vezivanja za ubikvitin-ligazu Svrab [19] i klatrinski adapterski kompleks 3,[20] ali je vjerojatno poremećen i nepotreban za aktivnost kinaze.[21] Domen kinaza može se podijeliti na N-terminalne i C-završne režnjeve sa ATP veznim žljebom i navodnim fosfatidilinositolskim veznim džepom između . C-režanj domena kinaza sadrži dodatni bočni hidrofobni džep bez još dodijeljene posebne funkcije.[18][22]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000155252 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025178 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Barylko B, Gerber SH, Binns DD, Grichine N, Khvotchev M, Sudhof TC, Albanesi JP (maj 2001). "A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans". J Biol Chem. 276 (11): 7705–8. doi:10.1074/jbc.C000861200. PMID 11244087.
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- ^ "Entrez Gene: PI4KII phosphatidylinositol 4-kinase type II".
- ^ "UniProt, Q9BTU6". Pristupljeno 3. 9. 2021.
- ^ Balla, A; Tuymetova, G; Barshishat, M; Geiszt, M; Balla, T (31. 5. 2002). "Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments". The Journal of Biological Chemistry. 277 (22): 20041–50. doi:10.1074/jbc.m111807200. PMID 11923287.
- ^ Barylko, B; Mao, YS; Wlodarski, P; Jung, G; Binns, DD; Sun, HQ; Yin, HL; Albanesi, JP (10. 4. 2009). "Palmitoylation controls the catalytic activity and subcellular distribution of phosphatidylinositol 4-kinase II{alpha}". The Journal of Biological Chemistry. 284 (15): 9994–10003. doi:10.1074/jbc.M900724200. PMC 2665123. PMID 19211550.
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- ^ Minogue, S; Waugh, MG; De Matteis, MA; Stephens, DJ; Berditchevski, F; Hsuan, JJ (1. 2. 2006). "Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor". Journal of Cell Science. 119 (Pt 3): 571–81. doi:10.1242/jcs.02752. PMID 16443754.
- ^ Pan, W; Choi, SC; Wang, H; Qin, Y; Volpicelli-Daley, L; Swan, L; Lucast, L; Khoo, C; Zhang, X; Li, L; Abrams, CS; Sokol, SY; Wu, D (5. 9. 2008). "Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation". Science. 321 (5894): 1350–3. doi:10.1126/science.1160741. PMC 2532521. PMID 18772438.
- ^ Li, J; Lu, Y; Zhang, J; Kang, H; Qin, Z; Chen, C (29. 4. 2010). "PI4KIIalpha is a novel regulator of tumor growth by its action on angiogenesis and HIF-1alpha regulation". Oncogene. 29 (17): 2550–9. doi:10.1038/onc.2010.14. PMID 20154717.
- ^ Simons, JP; Al-Shawi, R; Minogue, S; Waugh, MG; Wiedemann, C; Evangelou, S; Loesch, A; Sihra, TS; King, R; Warner, TT; Hsuan, JJ (14. 7. 2009). "Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons". Proceedings of the National Academy of Sciences of the United States of America. 106 (28): 11535–9. doi:10.1073/pnas.0903011106. PMC 2710652. PMID 19581584.
- ^ Jović, M; Kean, MJ; Szentpetery, Z; Polevoy, G; Gingras, AC; Brill, JA; Balla, T (april 2012). "Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase". Molecular Biology of the Cell. 23 (8): 1533–45. doi:10.1091/mbc.E11-06-0553. PMC 3327330. PMID 22337770.
- ^ Wu, B; Kitagawa, K; Zhang, NY; Liu, B; Inagaki, C (decembar 2004). "Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity". Journal of Neurochemistry. 91 (5): 1164–70. doi:10.1111/j.1471-4159.2004.02805.x. PMID 15569259. S2CID 36690417.
- ^ a b Baumlova, A.; Chalupska, D.; Rozycki, B.; Jovic, M.; Wisniewski, E.; Klima, M.; Dubankova, A.; Kloer, D. P.; Nencka, R.; Balla, T.; Boura, E. (28. 8. 2014). "The crystal structure of the phosphatidylinositol 4-kinase II". EMBO Reports. 15 (10): 1085–1092. doi:10.15252/embr.201438841. PMC 4253849. PMID 25168678.
- ^ Mössinger, Julia; Wieffer, Marnix; Krause, Eberhard; Freund, Christian; Gerth, Fabian; Krauss, Michael; Haucke, Volker (13. 11. 2012). "Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch". EMBO Reports. 13 (12): 1087–1094. doi:10.1038/embor.2012.164. PMC 3512407. PMID 23146885.
- ^ Craige, B.; Salazar, G.; Faundez, V. (1. 4. 2008). "Phosphatidylinositol-4-Kinase Type II Alpha Contains an AP-3-sorting Motif and a Kinase Domain That Are Both Required for Endosome Traffic". Molecular Biology of the Cell. 19 (4): 1415–1426. doi:10.1091/mbc.E07-12-1239. PMC 2291421. PMID 18256276.
- ^ Barylko, B; Wlodarski, P; Binns, DD; Gerber, SH; Earnest, S; Sudhof, TC; Grichine, N; Albanesi, JP (15. 11. 2002). "Analysis of the catalytic domain of phosphatidylinositol 4-kinase type II". The Journal of Biological Chemistry. 277 (46): 44366–75. doi:10.1074/jbc.m203241200. PMID 12215430.
- ^ Zhou, Qiangjun; Li, Jiangmei; Yu, Hang; Zhai, Yujia; Gao, Zhen; Liu, Yanxin; Pang, Xiaoyun; Zhang, Lunfeng; Schulten, Klaus; Sun, Fei; Chen, Chang (28. 3. 2014). "Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα". Nature Communications. 5: 3552. doi:10.1038/ncomms4552. PMC 3974213. PMID 24675427.
Dopunska literatuara
uredi- Balla, A; Balla, T (juli 2006). "Phosphatidylinositol 4-kinases: old enzymes with emerging functions". Trends in Cell Biology. 16 (7): 351–61. doi:10.1016/j.tcb.2006.05.003. PMID 16793271.
- Balla, T (juli 2013). "Phosphoinositides: tiny lipids with giant impact on cell regulation". Physiological Reviews. 93 (3): 1019–137. doi:10.1152/physrev.00028.2012. PMC 3962547. PMID 23899561.
- Minogue, S; Waugh, MG (2012). The phosphatidylinositol 4-kinases: don't call it a comeback. Subcellular Biochemistry. 58. str. 1–24. doi:10.1007/978-94-007-3012-0_1. ISBN 978-94-007-3011-3. PMID 22403072.
- Kutateladze, TG (juli 2010). "Translation of the phosphoinositide code by PI effectors". Nature Chemical Biology. 6 (7): 507–13. doi:10.1038/nchembio.390. PMC 3182472. PMID 20559318.
- Tan, J; Brill, JA (2014). "Cinderella story: PI4P goes from precursor to key signaling molecule". Critical Reviews in Biochemistry and Molecular Biology. 49 (1): 33–58. doi:10.3109/10409238.2013.853024. PMID 24219382. S2CID 207506490.