ACTG1
Gama-aktin je protein koji je kod ljudi kodiran genom ACTG1.[5] Gama-aktin je široko eksprimiran u ćelijskim citoskeletima mnogih tkiva; u ćelijama prugastih mišića odraslih. gama-aktin je lokaliziran na Z-disk i kostamerne strukture, koje su odgovorne za transdukciju i prenos sile u mišićnim ćelijama. Mutacije u ACTG1 povezane su sa nesindromnim gubitkom sluha i Baraitser-Winterovim sindromom, kao i podložnošću adolescentnih pacijenata toksičnosti vinkristina.
Struktura
urediAminokiselimska selvenca
Dužina polipeptidnog lanca je 375 aminokiselina, a molekulska težina 41.793 Da.[6]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MEEEIAALVI | DNGSGMCKAG | FAGDDAPRAV | FPSIVGRPRH | QGVMVGMGQK | ||||
| DSYVGDEAQS | KRGILTLKYP | IEHGIVTNWD | DMEKIWHHTF | YNELRVAPEE | ||||
| HPVLLTEAPL | NPKANREKMT | QIMFETFNTP | AMYVAIQAVL | SLYASGRTTG | ||||
| IVMDSGDGVT | HTVPIYEGYA | LPHAILRLDL | AGRDLTDYLM | KILTERGYSF | ||||
| TTTAEREIVR | DIKEKLCYVA | LDFEQEMATA | ASSSSLEKSY | ELPDGQVITI | ||||
| GNERFRCPEA | LFQPSFLGME | SCGIHETTFN | SIMKCDVDIR | KDLYANTVLS | ||||
| GGTTMYPGIA | DRMQKEITAL | APSTMKIKII | APPERKYSVW | IGGSILASLS | ||||
| TFQQMWISKQ | EYDESGPSIV | HRKCF |
- Simboli
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
Aktini su visoko konzervirani proteini koji sudjeluju u različitim tipovima pokretljivosti ćelija i održavanju citoskeleta. U kičmenjaka identificirane su tri glavne grupe aktintinskih izoformi, alfa, beta i gama.[7]
Alfa aktini nalaze se u mišićnim tkivima i glavni su sastojak kontraktilnog aparata sarkomera. Beta i gama aktini koegzistiraju u većini tipova ćelija kao komponente citoskeleta i kao posrednici unutrašnje ćelijske pokretljivosti. Aktin gama 1, kodiran ovim genom, nalazi se u u citoplazmi mišićnih ćelija i u mišićnim ćelijama na kostamernim strukturama ili u poprečnim tačkama adhezije ćelijsa–ćelija koje idu okomito na dugu os miocita.[8][9][10]
Funkcija
urediU miocitima, sarkomere se pridržavaju sarkolemaama putem kostamera, koje se poravnavaju na Z-diskovima i M-linijama.[11] Dvije primarne citoskeletne komponente kostamera su dezmin, srednji filament i gama-aktinski mikrofilamenti.[12] Pokazalo se da je gama-aktin u interakciji sa drugim kostamernim proteinom, distrofinom presudan za kostamerno formiranje mehanički jakih veza između citoskeleta i sarkolema i membrana.[13][14] Dodatne studije pokazale su da se gama-aktin kolokalira sa alfa-aktininom i GFP - označenim gama aktinom lokalizovanim na Z-diskovima , dok je GFP - alfa-aktin na šiljastim krajevima tankih filamenata, što ukazuje da se gama aktin specifično lokalizuje na Z-diskovima u prugastim mišićnim ćelijama.[15][16][17]
Smatra se da tokom razvoja miocita, gama-aktin ima ulogu u organizaciji razvijanja i sastavljanju razvijanja sarkomera, što se dijelom dokazuje i njegovom ranom kolokalizacijom sa alfa-aktininom.[18] Gama-aktin se na kraju zamjenjuje izoformama sarkomernog alfa-aktina,[19][20][21] sa niskim nivoima gama-aktina koji perzistiraju u miocitima odraslih koji se povezuju sa Z-diskovima i kostamernim domenima.[15][22][23]
Bolji uvid u funkciju gama-aktina u mišićima proizašao je iz studija koje koriste transgenezu. U skeletnomišićnom specifičnom gama-aktinu kod nokaut-miševa, ove životinje nisu pokazale uočljive abnormalnosti u razvoju; međutim, nokaut-miševi pokazali su slabost mišićnih vlakana i nekrozu, zajedno sa smanjenom izometrijskom silom trzanja, poremećene intrafibrilske i interfibrilske veze između miocita i miopatija .[24]
Klinički značaj
urediU pacijenata sa oštećenjem sluha identificirana je autosomno dominantna mutacija u ACTG1 u lokusu DFNA20/ 26 na 17q25-qter. Mutacija Thr 278 Ile identificirana je u proteinskom heliksu 9 gama-aktina, za koji se predviđa da će promeniti strukturu proteina. Ova studija identificirala je prvu bolest koja uzrokuje mutaciju gama-aktina i podvlači važnost gama-aktina kao strukturnih elemenata u trepljstim ćelijama unutrašnjeg uha.[25] Od tada su i druge ACTG1 mutacije povezane sa nesindromnim oštećenjem sluha, uključujući Met 305 Thr.[26]
Misens mutacije u ACTG1 na Ser 155 Phe također je identifikovana kod pacijenata sa Baraitser-Winterovim sindromom, što je poremećaj u razvoju koji karakteriše urođena ptoza, prekomjerno zasvođene obrve, hipertelorizam, okularni kolobom, lizencefalija, nizak rast, napadi i gubitak sluha.[27][28]
Diferencijalna ekspresija ACTG1-ove iRNK također je identifikovana kod pacijenata sa sporadičnom amiotrofnom lateralnom sklerozom, razarajućom bolešću sa nepoznatom uzročnošću, koristeći sofisticirani bioinformatički pristup koji koristi Affymetrix dugooligonukleotidnog BaFL metoda.[29]
Jednonukleotidni polimorfizmi u ACTG povezani su s toksičnošću vinkristina, što je dio standardnog režima liječenja za djetinjstvenu akutne limfoblastne leukemije. Neurotoksičnost bila je češća kod pacijenata koji su bili nositelji mutacije ACTG1 u sekvenci Gly 310 Ala, što sugerira da ovo može imati ulogu u ishodima pacijenta oliječenih vinkristinom.[30]
Interakcije
urediDokazano je da ACTG1 komunicira sa:
Također pogledajte
urediReference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000184009 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062825 - 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.
- ^ "Entrez Gene: ACTG1 actin, gamma 1".
- ^ "UniProt, P63261". Pristupljeno 25. 6. 2021.
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Vanjski linkovi
uredi- Lokacija ljudskog genoma ACTG1 i stranica sa detaljima o genu ACTG1 u UCSC Genome Browseru.