ACVR1

ACVR1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	3H9R, 3MTF, 3OOM, 3Q4U, 4BGG, 4C02, 4DYM
Identifikatori
Aliasi	ACVR1
Vanjski ID-jevi	OMIM: 102576 MGI: 87911 HomoloGene: 7 GeneCards: ACVR1
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	157,876,330 bp
Lokacija gena (miš)
Hrom.	Hromosom 2 (miš)
Kraj	58,457,169 bp
Ontologija gena
Molekularna funkcija	• aktivnost sa transferazom; • protein kinase activity; • activin receptor activity, type I; • nucleotide binding; • protein homodimerization activity; • growth factor binding; • activin binding; • vezivanje iona metala; • kinase activity; • peptide hormone binding; • protein serine/threonine kinase activity; • transmembrane receptor protein serine/threonine kinase activity; • transforming growth factor beta receptor activity, type I; • GO:0001948, GO:0016582 vezivanje za proteine; • ATP binding; • transforming growth factor beta binding; • SMAD binding; • transforming growth factor beta-activated receptor activity; • BMP receptor activity;
Ćelijska komponenta	• integral component of membrane; • membrana; • apical part of cell; • integral component of plasma membrane; • activin receptor complex; • receptor complex;
Biološki proces	• germ cell development; • pathway-restricted SMAD protein phosphorylation; • positive regulation of bone mineralization; • Fosforilacija; • positive regulation of cell migration; • mesoderm formation; • gastrulation with mouth forming second; • negative regulation of extrinsic apoptotic signaling pathway; • endocardial cushion cell fate commitment; • cellular response to BMP stimulus; • in utero embryonic development; • positive regulation of determination of dorsal identity; • mitral valve morphogenesis; • smooth muscle cell differentiation; • BMP signaling pathway; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • protein phosphorylation; • negative regulation of activin receptor signaling pathway; • heart development; • determination of left/right symmetry; • positive regulation of osteoblast differentiation; • transmembrane receptor protein serine/threonine kinase signaling pathway; • acute inflammatory response; • Gastrulacija; • embryonic heart tube morphogenesis; • neural crest cell migration; • cardiac muscle cell fate commitment; • branching involved in blood vessel morphogenesis; • negative regulation of signal transduction; • regulation of ossification; • peptidyl-threonine phosphorylation; • mesoderm development; • transforming growth factor beta receptor signaling pathway; • pharyngeal system development; • activin receptor signaling pathway; • outflow tract septum morphogenesis; • atrioventricular valve morphogenesis; • endocardial cushion morphogenesis; • endocardial cushion fusion; • atrial septum primum morphogenesis; • positive regulation of pathway-restricted SMAD protein phosphorylation; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • ventricular septum morphogenesis; • BMP signaling pathway involved in heart development; • positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation; • G1/S transition of mitotic cell cycle; • pattern specification process;
	Izvori:Amigo / QuickGO
Ortolozi
	90
	11477
	ENSG00000115170
	ENSMUSG00000026836
	Q04771
	P37172
NM_001105; NM_001111067; NM_001347663; NM_001347664; NM_001347665;
	NM_001347666; NM_001347667
	NM_001110204; NM_001110205; NM_007394; NM_001355048; NM_001355049
NP_001096; NP_001104537; NP_001334592; NP_001334593; NP_001334594;
	NP_001334595; NP_001334596
	NP_001103674; NP_001103675; NP_031420; NP_001341977; NP_001341978
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Tip I receptora aktivina A (ACVR1) jest protein/enzim koji je kod ljudi kodiran genom ACVR1 /ALK-2 (eng. skr. odActivin receptor-like kinase-2) sa hromosoma 4.^[5] ACVR1 je vezan za 2q23-24 regju genoma.^[6] Ovaj protein je važan na putu koštano-morfogenog proteina (BMP) koji je odgovoran za razvoj i popravak koštanog sistema. Dok su modeli s izbacivanjem s ovim genom u toku, gen ACVR1 povezan je s progresivnom fibrodysplasia ossificans, bolešću koju karakterizira stvaranje heterotopne kosti u cijelom tijelu.^[6] To je koštani morfogenetski proteinski receptor tip 1.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 509 aminokiselina, а molekulska težina 57.153 Da.^[7]

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
MVDGVMILPV	LIMIALPSPS	MEDEKPKVNP	KLYMCVCEGL	SCGNEDHCEG
QQCFSSLSIN	DGFHVYQKGC	FQVYEQGKMT	CKTPPSPGQA	VECCQGDWCN
RNITAQLPTK	GKSFPGTQNF	HLEVGLIILS	VVFAVCLLAC	LLGVALRKFK
RRNQERLNPR	DVEYGTIEGL	ITTNVGDSTL	ADLLDHSCTS	GSGSGLPFLV
QRTVARQITL	LECVGKGRYG	EVWRGSWQGE	NVAVKIFSSR	DEKSWFRETE
LYNTVMLRHE	NILGFIASDM	TSRHSSTQLW	LITHYHEMGS	LYDYLQLTTL
DTVSCLRIVL	SIASGLAHLH	IEIFGTQGKP	AIAHRDLKSK	NILVKKNGQC
CIADLGLAVM	HSQSTNQLDV	GNNPRVGTKR	YMAPEVLDET	IQVDCFDSYK
RVDIWAFGLV	LWEVARRMVS	NGIVEDYKPP	FYDVVPNDPS	FEDMRKVVCV
DQQRPNIPNR	WFSDPTLTSL	AKLMKECWYQ	NPSARLTALR	IKKTLTKIDN
SLDKLKTDC

Funkcija

Aktivini su dimerni faktori rasta i diferencijacije koji pripadaju transformirajućim faktorima rasta-beta (TGF-beta), natporodici strukturno povezanih signalnih proteina. Aktivini signaliziraju preko heteromernog kompleksa receptora serin-kinaza koji uključuju najmanje dva tipa I (I i IB) i dva tipa II (II i IIB) receptora. Svi ovi receptori su transmembranski proteini, sastavljeni od ligand-vezujućeg vančelijskog domenasa regijom bogatom cisteinom, transmembranski domen i citoplazmatski domen sa predviđenom specifičnošću serina / treonina. Receptori tipa I neophodni su za signalizaciju, a tipa II za vezivanje liganda i za ekspresiju receptora tipa I. Nakon vezivanja liganda, receptori tipa I i II formiraju stabilan kompleks, što rezultira fosforilacijama receptora tipa I II. Ovaj gen kodira receptor aktivin A tipa I koji signalizira određeni transkripcijski odgovor zajedno s receptorima aktivina tipa II.^[8]

Signalizacija

ACVR1 prenosi signale BMP). BMP se vežu za ili ACVR2A / ACVR2B ili za BMPR2, a zatim tvore kompleks s ACVR1. Nastavljaju regrutiranje R-SMAD SMAD1, SMAD2, SMAD3 ili SMAD6.^[9]

Klinički značaj

Mutacije pojačanja funkcije u genu ACVR1/ALK2 odgovorne su za nasljednu bolest progresivna fibrodisplasia ossificans.^[10] Pacijenti sa tipskim FOP imau zamjenu aminokiseline arginin histidinnom na proteinskoj poziciji 206 (tačkasta mutacija).^[11]^[12] Ovo izaziva promjenu u kritičnom glicin-serin aktivacijskom domenu proteina, što će uzrokovati da se protein manje čvrsto veže za svoj inhibitorni ligand (FKBP12) i na taj način pretjerano aktivira BMP/SMAD-ni put.^[6] Posljedica ove prekomjerne aktivacije je da se endotelne ćelije transformiraju u mezenhimne matične ćelije, a zatim u kost.^[13] Atipske mutacije koje uključuju druge ostatke djeluju slično – uzrokujući da se protein zaglavi u svojoj aktivnoj konformaciji, unatoč tome što nema BMP-a.^[14]

Mutacije u genu ACVR1 također su povezane s rakom, što s posebno odnosi na difuzni unutrašnji pontinski gliom (DIPG).^[15]^[16]^[17]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115170 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000026836 - 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.
^ ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (oktobar 1993). "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. PMID 8397373.
^ ^a ^b ^c Pignolo, Robert J. (juni 2013). "Fibrodysplasia Ossificans Progressiva: Diagnosis, Management, and Therapeutic Horizons". Pediatr Endocrinol Rev. 10 Suppl 2: 437–48. PMC 3995352. PMID 23858627.
^ "UniProt, Q04771" (jezik: engleski). Pristupljeno 21. 10. 2021.
^ "Entrez Gene: ACVR1 (activin A receptor, type I)".
^ Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (juli 2002). "SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7". Molecular Pharmacology. 62 (1): 65–74. doi:10.1124/mol.62.1.65. PMID 12065756.
^ Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS (maj 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics. 38 (5): 525–7. doi:10.1038/ng1783. PMID 16642017. S2CID 41579747.
^ Shore, Eileen M.; Xu, Meiqi; Feldman, George J.; Fenstermacher, David A.; Cho, Tae-Joon; Choi, In Ho; Connor, J. Michael; Delai, Patricia; Glaser, David L.; LeMerrer, Martine; Morhart, Rolf (maj 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics (jezik: engleski). 38 (5): 525–527. doi:10.1038/ng1783. ISSN 1546-1718. PMID 16642017. S2CID 41579747.
^ "News Release of FOP's Cause". Arhivirano s originala, 13. 1. 2012. Pristupljeno 29. 2. 2012.
^ van Dinther M, Visser N, de Gorter DJ, Doorn J, Goumans MJ, de Boer J, ten Dijke P (juni 2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research. 25 (6): 1208–15. doi:10.1359/jbmr.091110. PMID 19929436. S2CID 207269687.
^ Petrie, KA; Lee, WH; Bullock, AN; Pointon, JJ; Smith, R; Russell, RG; Brown, MA; Wordsworth, BP; Triffitt, JT (2009). "Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients". PLOS ONE. 4 (3): e5005. Bibcode:2009PLoSO...4.5005P. doi:10.1371/journal.pone.0005005. PMC 2658887. PMID 19330033.
^ Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J (maj 2014). "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics. 46 (5): 457–61. doi:10.1038/ng.2925. PMC 4018681. PMID 24705252.
^ "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation.
^ Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, et al. (maj 2014). "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–6. doi:10.1038/ng.2936. PMC 3997489. PMID 24705254.

Vanjski linkovi

Lokacija ljudskog genoma ACVR1 i stranica sa detaljima o genu ACVR1 u UCSC Genome Browseru.
Q04771

Šablon:Modulatori natporodičnih receptora

Portal Biologija

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000115170 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000026836 - 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.

[pmid8397373-5] ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (oktobar 1993). "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. PMID 8397373.

[:0-6] Pignolo, Robert J. (juni 2013). "Fibrodysplasia Ossificans Progressiva: Diagnosis, Management, and Therapeutic Horizons". Pediatr Endocrinol Rev. 10 Suppl 2: 437–48. PMC 3995352. PMID 23858627.

[UniProt-7] "UniProt, Q04771" (jezik: engleski). Pristupljeno 21. 10. 2021.

[8] "Entrez Gene: ACVR1 (activin A receptor, type I)".

[pmid12065756-9] Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (juli 2002). "SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7". Molecular Pharmacology. 62 (1): 65–74. doi:10.1124/mol.62.1.65. PMID 12065756.

[ACVR1-10] Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS (maj 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics. 38 (5): 525–7. doi:10.1038/ng1783. PMID 16642017. S2CID 41579747.

[11] Shore, Eileen M.; Xu, Meiqi; Feldman, George J.; Fenstermacher, David A.; Cho, Tae-Joon; Choi, In Ho; Connor, J. Michael; Delai, Patricia; Glaser, David L.; LeMerrer, Martine; Morhart, Rolf (maj 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics (jezik: engleski). 38 (5): 525–527. doi:10.1038/ng1783. ISSN 1546-1718. PMID 16642017. S2CID 41579747.

[12] "News Release of FOP's Cause". Arhivirano s originala, 13. 1. 2012. Pristupljeno 29. 2. 2012.

[13] van Dinther M, Visser N, de Gorter DJ, Doorn J, Goumans MJ, de Boer J, ten Dijke P (juni 2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research. 25 (6): 1208–15. doi:10.1359/jbmr.091110. PMID 19929436. S2CID 207269687.

[14] Petrie, KA; Lee, WH; Bullock, AN; Pointon, JJ; Smith, R; Russell, RG; Brown, MA; Wordsworth, BP; Triffitt, JT (2009). "Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients". PLOS ONE. 4 (3): e5005. Bibcode:2009PLoSO...4.5005P. doi:10.1371/journal.pone.0005005. PMC 2658887. PMID 19330033.

[15] Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J (maj 2014). "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics. 46 (5): 457–61. doi:10.1038/ng.2925. PMC 4018681. PMID 24705252.

[urlCure_Brain_Cancer_-_News_-_Multiple_Breakthroughs_in_Childhood_Brain_Cancer_DIPG-16] "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation.

[pmid24705254-17] Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, et al. (maj 2014). "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–6. doi:10.1038/ng.2936. PMC 3997489. PMID 24705254.

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