GBP2

GBP2
Identifikatori
Aliasi	GBP2
Vanjski ID-jevi	OMIM: 600412 MGI: 102772 HomoloGene: 10289 GeneCards: GBP2
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	89,150,456 bp
Lokacija gena (miš)
Hrom.	Hromosom 3 (miš)
Kraj	142,343,769 bp
Ontologija gena
Molekularna funkcija	• nucleotide binding; • GTP binding; • GO:0001948, GO:0016582 vezivanje za proteine; • hydrolase activity; • GO:0006184 GTPase activity; • protein homodimerization activity;
Ćelijska komponenta	• Golđijeva membrana; • membrana; • nukleoplazma; • citosol; • actin cytoskeleton; • jedro; • citoplazma; • Golđijev aparat; • perinuklearno područje citoplazme; • symbiont-containing vacuole membrane; • GO:0016023 citoplazmatska vezikula;
Biološki proces	• type I interferon signaling pathway; • GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor; • interferon-gamma-mediated signaling pathway; • protein localization to nucleus; • cellular response to interferon-gamma; • cellular response to interleukin-1; • cellular response to tumor necrosis factor; • defense response to protozoan; • GO:0051637 defense response to Gram-positive bacterium;
	Izvori:Amigo / QuickGO
Ortolozi
	2634
	14469
	ENSG00000162645
	ENSMUSG00000028270
	P32456
	Q9Z0E6
	NM_004120
	NM_010260
	NP_004111
	NP_034390
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Interferonom-inducirani gvanilat-vezujući protein 2 jest protein koji je kod ljudi kodiran genom GBP2 sa hromosoma 1.^[5]^[6] GBP2 je gen koji se odnosi na natporodicu velikih GTPaza koje se mogu inducirati uglavnom interferonom gama.^[7]

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 591 aminokiselina, a molekulska težina 67.209 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
MAPEINLPGP	MSLIDNTKGQ	LVVNPEALKI	LSAITQPVVV	VAIVGLYRTG
KSYLMNKLAG	KKNGFSLGST	VKSHTKGIWM	WCVPHPKKPE	HTLVLLDTEG
LGDIEKGDNE	NDSWIFALAI	LLSSTFVYNS	MGTINQQAMD	QLHYVTELTD
RIKANSSPGN	NSVDDSADFV	SFFPAFVWTL	RDFTLELEVD	GEPITADDYL
ELSLKLRKGT	DKKSKSFNDP	RLCIRKFFPK	RKCFVFDWPA	PKKYLAHLEQ
LKEEELNPDF	IEQVAEFCSY	ILSHSNVKTL	SGGIPVNGPR	LESLVLTYVN
AISSGDLPCM	ENAVLALAQI	ENSAAVEKAI	AHYEQQMGQK	VQLPTETLQE
LLDLHRDSER	EAIEVFMKNS	FKDVDQMFQR	KLGAQLEARR	DDFCKQNSKA
SSDCCMALLQ	DIFGPLEEDV	KQGTFSKPGG	YRLFTQKLQE	LKNKYYQVPR
KGIQAKEVLK	KYLESKEDVA	DALLQTDQSL	SEKEKAIEVE	RIKAESAEAA
KKMLEEIQKK	NEEMMEQKEK	SYQEHVKQLT	EKMERDRAQL	MAEQEKTLAL
KLQEQERLLK	EGFENESKRL	QKDIWDIQMR	SKSLEPICNI	L

Struktura

Analiza sekvence GBP2 pokazala je prisustvo RNK-vezujućeg domena koji se sastoji od tri motiva prepoznavanja RNK (RRM) i SR domena. Amino terminal GBp2 dijeli četiri motiva ponavljanja Arg-Gly-Gly (RGG) i devet serinskih ostataka u kontekstu arginin/serinskih motiva.^[9]

SR domen GBP2 je mjesto fosforilacija za SR specifičnu protein-kinazu SRPK (sky1) koja usmjerava jedarnu lokalizaciju GBP2.

Svinjski GBP2 ima veliku sličnost u pogledu N-terminala koji je globulski domen i sadrži funkciju GTPaza. Međutim, C-terminal ima spiralni domen koji je manje konzerviran.^[10]

Funkcija

Interferoni su citokini koji imaju antivirusne efekte i inhibiraju ćelijsku proliferaciju tumora. Indukuju veliki broj gena u svojim ciljnim ćelijama, uključujući i one koji kodiraju gvanilat-vezujući protein (GBP). GBP se odlikuju sposobnošću da specifično vežu guaninske nukleotide (GMP, GDP i GTP). Protein kodiran ovim genom je GTPaza koja pretvara GTP u GDP i GMP.^[6] Osim toga, GBP2 gen može biti veza između površinskih ćelijskih receptore i unutarćelijskih efektora koji mogu prenijeti vanćelijske informacije u ćelije, kao i unutarćelijski signalni transdukcijski protein.^[11]

Studija na goveđem genu GBP2 pokazala je važnost GBP2 u regulaciji proliferacije ćelija i otpornosti na infekciju patogenom, kao što je Izlaganje antivirusnoj aktivnosti protiv virusa gripe.^[12]

GPB2 promovira oksidativno ubijanje i isporučuje antimikrobne peptide u autofagolizosom, pružajući široku zaštitu domaćina od različitih klasa patogena. Tokom virusne infekcije, porodica GBP (GBP1, GBP2 i GBP5) ima vitalnu ulogu u aktiviranju kanonskog i nekanonskog inflamasoma na odgovor na infekciju patogenom putem Chlamydia muridarum.^[13]

Lokalizacija

Gen GBP2 nalazi se u različitim odjeljcima u ćeliji: jedro, citosol i citoskelet, a također se dimer GBP2-GBP5 nalazi u Golgijevom aparatu.^[14]

Osim toga, za regulaciju unutarćelijske lokalizacije i membranske asocijacije GBP2 potrebna je i izoprenilacija.^[15]

Aktivacija

Mišji gen GBP2 nije samo visoko aktiviran interferon-gama tokom aktivacije makrofaga, već i stimulacijom Tol-likih receptore, faktora nekroze tumora (TNF) i interleukina-1 beta.^[16]

Ekspresija

Nakon stimulacije interferonom gama, mišji GPB2 eksprimira se u urođenim i prilagodljivim imunskim ćelijama.^[12]

Interakcija

Gen GBP2 može komunicirati sa RNK, preko domena RRM1 i RRM2. RRM2 domen može prepoznati osnovni motiv GGUC prisutan u RNK. Osim toga, identificiran je novi tip RRM domena koji može komunicirati sa kompleksom THO/TREX.^[17]

Gen GBp2 može surađivati sa TREX (transkripcija-eksport) kompleksom; multimerni kompleks ima različite transkripcijske i eksportne faktore kao što su Yra1 i Sub2.^[17]

Klinički značaj

Genska mutacija

Kod pacijenata s migrenom identificirana je misens mutacija GBP2 (A907G). U prvom koraku može dovesti do vazomotorne disfunkcije, a zatim do glavobolje.^[11]

Rak dojke

GBP2 se smatra kontrolnim faktorom za proliferaciju i širenje u tumorskoj ćeliji. Visoka ekspresija GBP2 povezana je s boljom dijagnozom raka dojke. P53 može regulirati GBP2 i imati esencijalnu ulogu u razvoju tumora, inhibicijom metaloproteinaze MM9 kao i NF-Kappa B i proteina Rac.^[18]

Nivo transkripcije GBP2 također je reguliran i putem dva faktora transkripcije STAT1 i IRF1. Ekspresija GBP2 ima jaku korelaciju sa metagenom T-ćelija što se čini povezanom sa infiltracijom T-ćelija u rak dojke.^[18]

Međutim, nedavna studija je pokazala da GBP2 može regulirati protein 1 (Drp1) povezan s dinaminom, kako bi blokirao translokaciju Drp1 u mitohondrije, što dovodi do slabljenja Drp1 ovisne mitohondrijske fisije i također invazija ćelija raka dojke.^[19]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000162645 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000028270 - 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.
^ Cheng YS, Patterson CE, Staeheli P (septembar 1991). "Interferon-induced guanylate-binding proteins lack an N(T)KXD consensus motif and bind GMP in addition to GDP and GTP". Molecular and Cellular Biology. 11 (9): 4717–25. doi:10.1128/mcb.11.9.4717. PMC 361367. PMID 1715024.
^ ^a ^b "Entrez Gene: GBP2 guanylate binding protein 2, interferon-inducible".
^ Kim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD (oktobar 2012). "IFN-inducible GTPases in host cell defense". Cell Host & Microbe. 12 (4): 432–44. doi:10.1016/j.chom.2012.09.007. PMC 349020. PMID 23084913.
^ "UniProt, P32456" (jezik: eng.). Pristupljeno 28. 11. 2021.CS1 održavanje: nepoznati jezik (link)
^ Windgassen M, Krebber H (mart 2003). "Identification of Gbp2 as a novel poly(A)+ RNA-binding protein involved in the cytoplasmic delivery of messenger RNAs in yeast". EMBO Reports. 4 (3): 278–83. doi:10.1038/sj.embor.embor763. PMC 1315891. PMID 12634846.
^ Ma G, Huang J, Sun N, Liu X, Zhu M, Wu Z, Zhao S (maj 2008). "Molecular characterization of the porcine GBP1 and GBP2 genes". Molecular Immunology. 45 (10): 2797–807. doi:10.1016/j.molimm.2008.02.007. PMID 18346789.
^ ^a ^b Jiang, Yue (januar 2016). "Six novel rare non-synonymous mutations for migraine without aura identified by exome sequencing". Journal of Neurogenetics. 29 (4): 188–194. doi:10.3109/01677063.2015.1122787. PMID 26814133. S2CID 207441191.
^ ^a ^b Praefcke GJ (novembar 2017). "Regulation of innate immune functions by guanylate-binding proteins". International Journal of Medical Microbiology. 308 (1): 237–245. doi:10.1016/j.ijmm.2017.10.013. PMID 29174633.
^ Man SM, Place DE, Kuriakose T, Kanneganti TD (januar 2017). "Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation". Journal of Leukocyte Biology. 101 (1): 143–150. doi:10.1189/jlb.4MR0516-223R. PMC 6608036. PMID 27418355.
^ "GBP2 Gene". GeneCards Human Gene Database. Pristupljeno 7. 11. 2018.
^ Britzen-Laurent N, Bauer M, Berton V, Fischer N, Syguda A, Reipschläger S, Naschberger E, Herrmann C, Stürzl M (decembar 2010). "Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner". PLOS ONE. 5 (12): e14246. Bibcode:2010PLoSO...514246B. doi:10.1371/journal.pone.0014246. PMC 2998424. PMID 21151871.
^ Degrandi D, Kravets E, Konermann C, Beuter-Gunia C, Klümpers V, Lahme S, Wischmann E, Mausberg AK, Beer-Hammer S, Pfeffer K (januar 2013). "Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication". Proceedings of the National Academy of Sciences of the United States of America. 110 (1): 294–9. Bibcode:2013PNAS..110..294D. doi:10.1073/pnas.1205635110. PMC 3538222. PMID 23248289.
^ ^a ^b Martínez-Lumbreras S, Taverniti V, Zorrilla S, Séraphin B, Pérez-Cañadillas JM (januar 2016). "Gbp2 interacts with THO/TREX through a novel type of RRM domain". Nucleic Acids Research. 44 (1): 437–48. doi:10.1093/nar/gkv1303. PMC 4705658. PMID 26602689.
^ ^a ^b Godoy P, Cadenas C, Hellwig B, Marchan R, Stewart J, Reif R, Lohr M, Gehrmann M, Rahnenführer J, Schmidt M, Hengstler JG (juli 2014). "Interferon-inducible guanylate binding protein (GBP2) is associated with better prognosis in breast cancer and indicates an efficient T cell response". Breast Cancer. 21 (4): 491–9. doi:10.1007/s12282-012-0404-8. PMID 23001506. S2CID 8338232.
^ Zhang J, Zhang Y, Wu W, Wang F, Liu X, Shui G, Nie C (oktobar 2017). "Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion". Cell Death & Disease. 8 (10): e3151. doi:10.1038/cddis.2017.559. PMC 5680924. PMID 29072687.

Dopunska literatura

Maruyama K, Sugano S (januar 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
Neun R, Richter MF, Staeheli P, Schwemmle M (juli 1996). "GTPase properties of the interferon-induced human guanylate-binding protein 2". FEBS Letters. 390 (1): 69–72. doi:10.1016/0014-5793(96)00628-X. PMID 8706832. S2CID 30513363.
Nitsche EM, Moquin A, Adams PS, Guenette RS, Lakins JN, Sinnecker GH, Kruse K, Tenniswood MP (maj 1996). "Differential display RT PCR of total RNA from human foreskin fibroblasts for investigation of androgen-dependent gene expression". American Journal of Medical Genetics. 63 (1): 231–8. doi:10.1002/(SICI)1096-8628(19960503)63:1<231::AID-AJMG40>3.0.CO;2-M. PMID 8723115.
Vestal DJ, Gorbacheva VY, Sen GC (novembar 2000). "Different subcellular localizations for the related interferon-induced GTPases, MuGBP-1 and MuGBP-2: implications for different functions?". Journal of Interferon & Cytokine Research. 20 (11): 991–1000. doi:10.1089/10799900050198435. PMID 11096456.
Lukasiewicz R, Velazquez-Dones A, Huynh N, Hagopian J, Fu XD, Adams J, Ghosh G (august 2007). "Structurally unique yeast and mammalian serine-arginine protein kinases catalyze evolutionarily conserved phosphorylation reactions". The Journal of Biological Chemistry. 282 (32): 23036–43. doi:10.1074/jbc.M611305200. PMID 17517895.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000162645 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000028270 - 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.

[pmid1715024-5] Cheng YS, Patterson CE, Staeheli P (septembar 1991). "Interferon-induced guanylate-binding proteins lack an N(T)KXD consensus motif and bind GMP in addition to GDP and GTP". Molecular and Cellular Biology. 11 (9): 4717–25. doi:10.1128/mcb.11.9.4717. PMC 361367. PMID 1715024.

[entrez-6] "Entrez Gene: GBP2 guanylate binding protein 2, interferon-inducible".

[7] Kim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD (oktobar 2012). "IFN-inducible GTPases in host cell defense". Cell Host & Microbe. 12 (4): 432–44. doi:10.1016/j.chom.2012.09.007. PMC 349020. PMID 23084913.

[UniProt-8] "UniProt, P32456" (jezik: eng.). Pristupljeno 28. 11. 2021.CS1 održavanje: nepoznati jezik (link)

[:1-9] Windgassen M, Krebber H (mart 2003). "Identification of Gbp2 as a novel poly(A)+ RNA-binding protein involved in the cytoplasmic delivery of messenger RNAs in yeast". EMBO Reports. 4 (3): 278–83. doi:10.1038/sj.embor.embor763. PMC 1315891. PMID 12634846.

[10] Ma G, Huang J, Sun N, Liu X, Zhu M, Wu Z, Zhao S (maj 2008). "Molecular characterization of the porcine GBP1 and GBP2 genes". Molecular Immunology. 45 (10): 2797–807. doi:10.1016/j.molimm.2008.02.007. PMID 18346789.

[:4-11] Jiang, Yue (januar 2016). "Six novel rare non-synonymous mutations for migraine without aura identified by exome sequencing". Journal of Neurogenetics. 29 (4): 188–194. doi:10.3109/01677063.2015.1122787. PMID 26814133. S2CID 207441191.

[:0-12] Praefcke GJ (novembar 2017). "Regulation of innate immune functions by guanylate-binding proteins". International Journal of Medical Microbiology. 308 (1): 237–245. doi:10.1016/j.ijmm.2017.10.013. PMID 29174633.

[13] Man SM, Place DE, Kuriakose T, Kanneganti TD (januar 2017). "Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation". Journal of Leukocyte Biology. 101 (1): 143–150. doi:10.1189/jlb.4MR0516-223R. PMC 6608036. PMID 27418355.

[14] "GBP2 Gene". GeneCards Human Gene Database. Pristupljeno 7. 11. 2018.

[15] Britzen-Laurent N, Bauer M, Berton V, Fischer N, Syguda A, Reipschläger S, Naschberger E, Herrmann C, Stürzl M (decembar 2010). "Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner". PLOS ONE. 5 (12): e14246. Bibcode:2010PLoSO...514246B. doi:10.1371/journal.pone.0014246. PMC 2998424. PMID 21151871.

[16] Degrandi D, Kravets E, Konermann C, Beuter-Gunia C, Klümpers V, Lahme S, Wischmann E, Mausberg AK, Beer-Hammer S, Pfeffer K (januar 2013). "Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication". Proceedings of the National Academy of Sciences of the United States of America. 110 (1): 294–9. Bibcode:2013PNAS..110..294D. doi:10.1073/pnas.1205635110. PMC 3538222. PMID 23248289.

[:2-17] Martínez-Lumbreras S, Taverniti V, Zorrilla S, Séraphin B, Pérez-Cañadillas JM (januar 2016). "Gbp2 interacts with THO/TREX through a novel type of RRM domain". Nucleic Acids Research. 44 (1): 437–48. doi:10.1093/nar/gkv1303. PMC 4705658. PMID 26602689.

[:3-18] Godoy P, Cadenas C, Hellwig B, Marchan R, Stewart J, Reif R, Lohr M, Gehrmann M, Rahnenführer J, Schmidt M, Hengstler JG (juli 2014). "Interferon-inducible guanylate binding protein (GBP2) is associated with better prognosis in breast cancer and indicates an efficient T cell response". Breast Cancer. 21 (4): 491–9. doi:10.1007/s12282-012-0404-8. PMID 23001506. S2CID 8338232.

[19] Zhang J, Zhang Y, Wu W, Wang F, Liu X, Shui G, Nie C (oktobar 2017). "Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion". Cell Death & Disease. 8 (10): e3151. doi:10.1038/cddis.2017.559. PMC 5680924. PMID 29072687.

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