ACVR1

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ACVR1
Protein ACVR1 PDB 3H9R.png
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

3H9R, 3MTF, 3OOM, 3Q4U, 4BGG, 4C02, 4DYM

Identifikatori
AliasiACVR1
Vanjski ID-jeviOMIM: 102576 MGI: 87911 HomoloGene: 7 GeneCards: ACVR1
Lokacija gena (čovjek)
Hromosom 2 (čovjek)
Hrom.Hromosom 2 (čovjek)[1]
Hromosom 2 (čovjek)
Genomska lokacija za ACVR1
Genomska lokacija za ACVR1
Bend2q24.1Početak157,736,251 bp[1]
Kraj157,876,330 bp[1]
Lokacija gena (miš)
Hromosom 2 (miš)
Hrom.Hromosom 2 (miš)[2]
Hromosom 2 (miš)
Genomska lokacija za ACVR1
Genomska lokacija za ACVR1
Bend2|2 C1.1Početak58,388,644 bp[2]
Kraj58,567,157 bp[2]
Ontologija gena
Molekularna funkcija transferase activity
protein kinase activity
activin receptor activity, type I
nucleotide binding
protein homodimerization activity
growth factor binding
activin binding
metal ion binding
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 protein binding
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
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
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
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_001105
NM_001111067
NM_001347663
NM_001347664
NM_001347665

NM_001347666
NM_001347667

NM_001110204
NM_001110205
NM_007394
NM_001355048
NM_001355049

RefSeq (bjelančevina)
NP_001096
NP_001104537
NP_001334592
NP_001334593
NP_001334594

NP_001334595
NP_001334596

NP_001103674
NP_001103675
NP_031420
NP_001341977
NP_001341978

Lokacija (UCSC)Chr 2: 157.74 – 157.88 MbChr 2: 58.39 – 58.57 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/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[uredi | uredi izvor]

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

1020304050
MVDGVMILPVLIMIALPSPSMEDEKPKVNPKLYMCVCEGLSCGNEDHCEG
QQCFSSLSINDGFHVYQKGCFQVYEQGKMTCKTPPSPGQAVECCQGDWCN
RNITAQLPTKGKSFPGTQNFHLEVGLIILSVVFAVCLLACLLGVALRKFK
RRNQERLNPRDVEYGTIEGLITTNVGDSTLADLLDHSCTSGSGSGLPFLV
QRTVARQITLLECVGKGRYGEVWRGSWQGENVAVKIFSSRDEKSWFRETE
LYNTVMLRHENILGFIASDMTSRHSSTQLWLITHYHEMGSLYDYLQLTTL
DTVSCLRIVLSIASGLAHLHIEIFGTQGKPAIAHRDLKSKNILVKKNGQC
CIADLGLAVMHSQSTNQLDVGNNPRVGTKRYMAPEVLDETIQVDCFDSYK
RVDIWAFGLVLWEVARRMVSNGIVEDYKPPFYDVVPNDPSFEDMRKVVCV
DQQRPNIPNRWFSDPTLTSLAKLMKECWYQNPSARLTALRIKKTLTKIDN
SLDKLKTDC

Funkcija[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000115170 - Ensembl, maj 2017
  2. ^ a b c 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.
  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.
  6. ^ 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.
  7. ^ "UniProt, Q04771" (jezik: engleski). Pristupljeno 21. 10. 2021.
  8. ^ "Entrez Gene: ACVR1 (activin A receptor, type I)".
  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.
  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.
  16. ^ "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation.
  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.

Vanjski linkovi[uredi | uredi izvor]

Šablon:Signalizacija TGF beta Šablon:Serin/treonin specifične protein-kinaze

Šablon:Modulatori natporodičnih receptora

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