PI4KB

PI4KB
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4D0L, 4D0M, 4WAE, 4WAG, 5C4G, 5C46, 5EUQ
Identifikatori
Aliasi	PI4KB
Vanjski ID-jevi	OMIM: 602758 MGI: 1334433 HomoloGene: 6741 GeneCards: PI4KB
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	151,327,715 bp
Lokacija gena (miš)
Hrom.	Hromosom 3 (miš)
Kraj	94,914,154 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• ATP binding; • GO:0001948, GO:0016582 vezivanje za proteine; • kinase activity; • nucleotide binding; • aktivnost sa transferazom; • 14-3-3 protein binding; • 1-phosphatidylinositol 4-kinase activity;
Ćelijska komponenta	• Endomembranski sistem; • mitochondrial outer membrane; • rough endoplasmic reticulum membrane; • endozom; • perinuklearno područje citoplazme; • citosol; • Endoplazmatski retikulum; • citoplazma; • Golđijev aparat; • mitohondrija; • membrana; • Golđijeva membrana; • intracellular anatomical structure;
Biološki proces	• phosphatidylinositol biosynthetic process; • phosphatidylinositol phosphate biosynthetic process; • receptor-mediated endocytosis; • Fosforilacija; • GO:0072468 Transdukcija signala; • phosphatidylinositol-mediated signaling;
	Izvori:Amigo / QuickGO
Ortolozi
	5298
	107650
	ENSG00000143393
	ENSMUSG00000038861
	Q9UBF8
	Q8BKC8
NM_001198773; NM_001198774; NM_001198775; NM_002651; NM_001330721;
	NM_001369623; NM_001369624; NM_001369625; NM_001369626; NM_001369628; NM_001369629
	NM_001293715; NM_001293716; NM_175356
NP_001185702; NP_001185703; NP_001185704; NP_001317650; NP_002642;
	NP_001356552; NP_001356553; NP_001356554; NP_001356555; NP_001356557; NP_001356558
	NP_001280644; NP_001280645; NP_780565
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Fosfatidilinozitol 4-kinaza beta jest enzim koji je kod ljudi kodiran genom PI4KB sa hromosoma 1.^[5]^[6]^[7]

Klasifikacija

Ovaj gen kodira fosfatidilinozitol 4-kinazu koja katalizira fosforilaciju fosfatidilinozitola na D-4 poziciji, dajući fosfatidilinozitol 4-fosfat (PI4P). Osim činjenice da PI4P služi kao prekursor za druge važne fosfoinozitide, kao što je fosfatidilinozitol 4,5-bisfosfat, fosfatidilinozitol 4-fosfatnih molekula, učestvuje 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

fosfatidilinozitol 4-kinaza alfa (PI4KA)
fosfatidilinozitol 4-kinaza beta (PI4KB)
fosfatidilinozitol 4-kinaza 2-alfa (PI4K2A)
fosfatidilinozitol 4-kinaza 2-beta (PI4K2B)

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 816 aminokiselina, a molekulska težina 91.379 Da.^[8]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MGDTVVEPAP	LKPTSEPTSG	PPGNNGGSLL	SVITEGVGEL	SVIDPEVAQK
ACQEVLEKVK	LLHGGVAVSS	RGTPLELVNG	DGVDSEIRCL	DDPPAQIREE
EDEMGAAVAS	GTAKGARRRR	QNNSAKQSWL	LRLFESKLFD	ISMAISYLYN
SKEPGVQAYI	GNRLFCFRNE	DVDFYLPQLL	NMYIHMDEDV	GDAIKPYIVH
RCRQSINFSL	QCALLLGAYS	SDMHISTQRH	SRGTKLRKLI	LSDELKPAHR
KRELPSLSPA	PDTGLSPSKR	THQRSKSDAT	ASISLSSNLK	RTASNPKVEN
EDEELSSSTE	SIDNSFSSPV	RLAPEREFIK	SLMAIGKRLA	TLPTKEQKTQ
RLISELSLLN	HKLPARVWLP	TAGFDHHVVR	VPHTQAVVLN	SKDKAPYLIY
VEVLECENFD	TTSVPARIPE	NRIRSTRSVE	NLPECGITHE	QRAGSFSTVP
NYDNDDEAWS	VDDIGELQVE	LPEVHTNSCD	NISQFSVDSI	TSQESKEPVF
IAAGDIRRRL	SEQLAHTPTA	FKRDPEDPSA	VALKEPWQEK	VRRIREGSPY
GHLPNWRLLS	VIVKCGDDLR	QELLAFQVLK	QLQSIWEQER	VPLWIKPYKI
LVISADSGMI	EPVVNAVSIH	QVKKQSQLSL	LDYFLQEHGS	YTTEAFLSAQ
RNFVQSCAGY	CLVCYLLQVK	DRHNGNILLD	AEGHIIHIDF	GFILSSSPRN
LGFETSAFKL	TTEFVDVMGG	LDGDMFNYYK	MLMLQGLIAA	RKHMDKVVQI
VEIMQQGSQL	PCFHGSSTIR	NLKERFHMSM	TEEQLQLLVE	QMVDGSMRSI
TTKLYDGFQY	LTNGIM

Struktura

PI4KB se sastoji od prolinom bogatog N-terminalne regije, centralnog spiralnog domena i kinaznog domena koji se nalazi na C-terminalnom području. N-terminalna regija sadrži fiziološki važno mjesto vezivanja za Golgijev adapterski protein ACBD3, ali je vjerovatno poremećen i neophodan za aktivnost kinaze. Centralni spiralni domen odgovoran je za interakciju sa malom gvanozin trifosfatazom Rab11. Kinazni domen može se podijeliti na N-terminalne i C-terminalne režnjeve sa ATP- veznim žljebom i navodnim fosfatidilinozitolski veznim džepom u rascjep između režnjeva.^[9] Osim toga, u ekstremnom C-terminalnom području PI4KB, identificiran je motiv ALPS, što pogoduje njegovoj povezanosti s nezasićenim ili slabo zbijenim regijama membrane.^[10]

Helikski i kinazni domeni fosfatidilinozitol 4-kinaze beta sa nukleozidnim analogom.
Heliksni domen obojen je u lososu, N-režanj kinaznog domena u zlatu, C -režanj u akvamarinu, specifični inhibitor vezan na aktivnom mjestu između režnjeva u štapiću. PDB kod: 4WAG.

Funkcija

Fosfatidilinozitol 4-kinaza beta (PI4KB) je rastvorljivi protein koji se kreće između citoplazme i jedra,^[11] i može se uključiti u membrane Golgijevog sistema, putem interakcija protein-protein, npr. sa malim GTP-vezujućim proteinima Arf1^[12] i Rab11,^[13] ili proteinom Golgijevog adaptera ACBD3.^[14]^[15] PI4KB može biti fosforiliran pomoću protein-kinaze D,^[16] koji podstiče interakciju sa 14-3-3 proteinom i stabilizaciju proteina u njegovoj aktivnoj konformaciji.^[17] U citoplazmi, PI4KB regulira promet iz Golgijevog sistema u plazmamembranu, međutim, ostaje da se utvrdi njegova jedarna funkcija.

Klinički značaj

Širok spektar jednolančanih RNK virusa (npr. pikornavirus], uključujući mnoge važne ljudske patogene, uzimaju ljudsku PI4KB kinazu za stvaranje specifičnih fosfatidilinozitol 4-fosfatom obogaćenih organela koje se nazivaju membranske mreže.^[18] Ove organele se zatim koriste kao specifične platforme za efikasnu replikaciju virusa unutar ćelije domaćina.

Nadalje, homolog PI4KB iz protozojskog parazita Plasmodium falciparum identificiran je kao meta imidopirazina, klase antimalarijskih spojeva.^[19]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000143393 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000038861 - 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.
^ Meyers R, Cantley LC (februar 1997). "Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase". The Journal of Biological Chemistry. 272 (7): 4384–90. doi:10.1074/jbc.272.7.4384. PMID 9020160.
^ Saito T, Seki N, Ishii H, Ohira M, Hayashi A, Kozuma S, Hori T (august 1997). "Complementary DNA cloning and chromosomal mapping of a novel phosphatidylinositol kinase gene". DNA Research. 4 (4): 301–5. doi:10.1093/dnares/4.4.301. PMID 9405938.
^ "Entrez Gene: PIK4CB phosphatidylinositol 4-kinase, catalytic, beta polypeptide".
^ "UniProt, Q9UBF8" (jezik: engleski). Pristupljeno 16. 12. 2021.
^ Burke JE, Inglis AJ, Perisic O, Masson GR, McLaughlin SH, Rutaganira F, Shokat KM, Williams RL (maj 2014). "Structures of PI4KIIIβ complexes show simultaneous recruitment of Rab11 and its effectors". Science. 344 (6187): 1035–8. doi:10.1126/science.1253397. PMC 4046302. PMID 24876499.
^ Mesmin B, Bigay J, Polidori J, Jamecna D, Lacas-Gervais S, Antonny B (novembar 2017). "Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP". The EMBO Journal. 36 (21): 3156–3174. doi:10.15252/embj.201796687. PMC 5666618. PMID 28978670.
^ de Graaf P, Klapisz EE, Schulz TK, Cremers AF, Verkleij AJ, van Bergen en Henegouwen PM (april 2002). "Nuclear localization of phosphatidylinositol 4-kinase beta". Journal of Cell Science. 115 (Pt 8): 1769–75. PMID 11950893.
^ Godi A, Pertile P, Meyers R, Marra P, Di Tullio G, Iurisci C, Luini A, Corda D, De Matteis MA (septembar 1999). "ARF mediates recruitment of PtdIns-4-OH kinase-beta and stimulates synthesis of PtdIns(4,5)P2 on the Golgi complex". Nature Cell Biology. 1 (5): 280–7. doi:10.1038/12993. PMID 10559940. S2CID 30441132.
^ de Graaf P, Zwart WT, van Dijken RA, Deneka M, Schulz TK, Geijsen N, Coffer PJ, Gadella BM, Verkleij AJ, van der Sluijs P, van Bergen en Henegouwen PM (april 2004). "Phosphatidylinositol 4-kinasebeta is critical for functional association of rab11 with the Golgi complex". Molecular Biology of the Cell. 15 (4): 2038–47. doi:10.1091/mbc.E03-12-0862. PMC 379297. PMID 14767056.
^ Sasaki J, Ishikawa K, Arita M, Taniguchi K (februar 2012). "ACBD3-mediated recruitment of PI4KB to picornavirus RNA replication sites". The EMBO Journal. 31 (3): 754–66. doi:10.1038/emboj.2011.429. PMC 3273392. PMID 22124328.
^ Greninger AL, Knudsen GM, Betegon M, Burlingame AL, DeRisi JL (april 2013). "ACBD3 interaction with TBC1 domain 22 protein is differentially affected by enteroviral and kobuviral 3A protein binding". mBio. 4 (2): e00098-13. doi:10.1128/mBio.00098-13. PMC 3622926. PMID 23572552.
^ Hausser A, Storz P, Märtens S, Link G, Toker A, Pfizenmaier K (septembar 2005). "Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIbeta at the Golgi complex". Nature Cell Biology. 7 (9): 880–6. doi:10.1038/ncb1289. PMC 1458033. PMID 16100512.
^ Hausser A, Link G, Hoene M, Russo C, Selchow O, Pfizenmaier K (septembar 2006). "Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase III beta protects from dephosphorylation and stabilizes lipid kinase activity". Journal of Cell Science. 119 (Pt 17): 3613–21. doi:10.1242/jcs.03104. PMID 16912074.
^ Hsu NY, Ilnytska O, Belov G, Santiana M, Chen YH, Takvorian PM, Pau C, van der Schaar H, Kaushik-Basu N, Balla T, Cameron CE, Ehrenfeld E, van Kuppeveld FJ, Altan-Bonnet N (maj 2010). "Viral reorganization of the secretory pathway generates distinct organelles for RNA replication". Cell. 141 (5): 799–811. doi:10.1016/j.cell.2010.03.050. PMC 2982146. PMID 20510927.
^ McNamara CW, Lee MC, Lim CS, Lim SH, Roland J, Simon O, Yeung BK, Chatterjee AK, McCormack SL, Manary MJ, Zeeman AM, Dechering KJ, Kumar TS, Henrich PP, Gagaring K, Ibanez M, Kato N, Kuhen KL, Fischli C, Nagle A, Rottmann M, Plouffe DM, Bursulaya B, Meister S, Rameh L, Trappe J, Haasen D, Timmerman M, Sauerwein RW, Suwanarusk R, Russell B, Renia L, Nosten F, Tully DC, Kocken CH, Glynne RJ, Bodenreider C, Fidock DA, Diagana TT, Winzeler EA (decembar 2013). "Targeting Plasmodium PI(4)K to eliminate malaria". Nature. 504 (7479): 248–253. doi:10.1038/nature12782. PMC 3940870. PMID 24284631.

Dopunska literatura

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.
Altan-Bonnet N, Balla T (juli 2012). "Phosphatidylinositol 4-kinases: hostages harnessed to build panviral replication platforms". Trends in Biochemical Sciences. 37 (7): 293–302. doi:10.1016/j.tibs.2012.03.004. PMC 3389303. PMID 22633842.
Minogue S, Waugh MG (2012). "The phosphatidylinositol 4-kinases: don't call it a comeback". Subcellular Biochemistry. 58: 1–24. doi:10.1007/978-94-007-3012-0_1. ISBN 978-94-007-3011-3. PMID 22403072. journal zahtijeva |journal= (pomoć)
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.

Vanjski linkovi

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000143393 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000038861 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9020160-5] Meyers R, Cantley LC (februar 1997). "Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase". The Journal of Biological Chemistry. 272 (7): 4384–90. doi:10.1074/jbc.272.7.4384. PMID 9020160.

[pmid9405938-6] Saito T, Seki N, Ishii H, Ohira M, Hayashi A, Kozuma S, Hori T (august 1997). "Complementary DNA cloning and chromosomal mapping of a novel phosphatidylinositol kinase gene". DNA Research. 4 (4): 301–5. doi:10.1093/dnares/4.4.301. PMID 9405938.

[entrez-7] "Entrez Gene: PIK4CB phosphatidylinositol 4-kinase, catalytic, beta polypeptide".

[UniProt-8] "UniProt, Q9UBF8" (jezik: engleski). Pristupljeno 16. 12. 2021.

[9] Burke JE, Inglis AJ, Perisic O, Masson GR, McLaughlin SH, Rutaganira F, Shokat KM, Williams RL (maj 2014). "Structures of PI4KIIIβ complexes show simultaneous recruitment of Rab11 and its effectors". Science. 344 (6187): 1035–8. doi:10.1126/science.1253397. PMC 4046302. PMID 24876499.

[10] Mesmin B, Bigay J, Polidori J, Jamecna D, Lacas-Gervais S, Antonny B (novembar 2017). "Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP". The EMBO Journal. 36 (21): 3156–3174. doi:10.15252/embj.201796687. PMC 5666618. PMID 28978670.

[11] Graaf P, Klapisz EE, Schulz TK, Cremers AF, Verkleij AJ, van Bergen en Henegouwen PM (april 2002). "Nuclear localization of phosphatidylinositol 4-kinase beta". Journal of Cell Science. 115 (Pt 8): 1769–75. PMID 11950893.

[12] Godi A, Pertile P, Meyers R, Marra P, Di Tullio G, Iurisci C, Luini A, Corda D, De Matteis MA (septembar 1999). "ARF mediates recruitment of PtdIns-4-OH kinase-beta and stimulates synthesis of PtdIns(4,5)P2 on the Golgi complex". Nature Cell Biology. 1 (5): 280–7. doi:10.1038/12993. PMID 10559940. S2CID 30441132.

[13] Graaf P, Zwart WT, van Dijken RA, Deneka M, Schulz TK, Geijsen N, Coffer PJ, Gadella BM, Verkleij AJ, van der Sluijs P, van Bergen en Henegouwen PM (april 2004). "Phosphatidylinositol 4-kinasebeta is critical for functional association of rab11 with the Golgi complex". Molecular Biology of the Cell. 15 (4): 2038–47. doi:10.1091/mbc.E03-12-0862. PMC 379297. PMID 14767056.

[14] Sasaki J, Ishikawa K, Arita M, Taniguchi K (februar 2012). "ACBD3-mediated recruitment of PI4KB to picornavirus RNA replication sites". The EMBO Journal. 31 (3): 754–66. doi:10.1038/emboj.2011.429. PMC 3273392. PMID 22124328.

[15] Greninger AL, Knudsen GM, Betegon M, Burlingame AL, DeRisi JL (april 2013). "ACBD3 interaction with TBC1 domain 22 protein is differentially affected by enteroviral and kobuviral 3A protein binding". mBio. 4 (2): e00098-13. doi:10.1128/mBio.00098-13. PMC 3622926. PMID 23572552.

[16] Hausser A, Storz P, Märtens S, Link G, Toker A, Pfizenmaier K (septembar 2005). "Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIbeta at the Golgi complex". Nature Cell Biology. 7 (9): 880–6. doi:10.1038/ncb1289. PMC 1458033. PMID 16100512.

[17] Hausser A, Link G, Hoene M, Russo C, Selchow O, Pfizenmaier K (septembar 2006). "Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase III beta protects from dephosphorylation and stabilizes lipid kinase activity". Journal of Cell Science. 119 (Pt 17): 3613–21. doi:10.1242/jcs.03104. PMID 16912074.

[18] Hsu NY, Ilnytska O, Belov G, Santiana M, Chen YH, Takvorian PM, Pau C, van der Schaar H, Kaushik-Basu N, Balla T, Cameron CE, Ehrenfeld E, van Kuppeveld FJ, Altan-Bonnet N (maj 2010). "Viral reorganization of the secretory pathway generates distinct organelles for RNA replication". Cell. 141 (5): 799–811. doi:10.1016/j.cell.2010.03.050. PMC 2982146. PMID 20510927.

[19] McNamara CW, Lee MC, Lim CS, Lim SH, Roland J, Simon O, Yeung BK, Chatterjee AK, McCormack SL, Manary MJ, Zeeman AM, Dechering KJ, Kumar TS, Henrich PP, Gagaring K, Ibanez M, Kato N, Kuhen KL, Fischli C, Nagle A, Rottmann M, Plouffe DM, Bursulaya B, Meister S, Rameh L, Trappe J, Haasen D, Timmerman M, Sauerwein RW, Suwanarusk R, Russell B, Renia L, Nosten F, Tully DC, Kocken CH, Glynne RJ, Bodenreider C, Fidock DA, Diagana TT, Winzeler EA (decembar 2013). "Targeting Plasmodium PI(4)K to eliminate malaria". Nature. 504 (7479): 248–253. doi:10.1038/nature12782. PMC 3940870. PMID 24284631.

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