UBE3A

UBE3A
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4GIZ, 1C4Z, 1D5F, 1EQX, 2KR1
Identifikatori
Aliasi	UBE3A
Vanjski ID-jevi	OMIM: 601623 MGI: 105098 HomoloGene: 7988 GeneCards: UBE3A
Lokacija gena (čovjek)
Hrom.	Hromosom 15 (čovjek)
Kraj	25,439,051 bp
Lokacija gena (miš)
Hrom.	Hromosom 7 (miš)
Kraj	59,311,536 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• vezivanje iona metala; • GO:0001105 transcription coactivator activity; • GO:0050372 aktivnost sa transferazom ubikvitina; • GO:0001948, GO:0016582 vezivanje za proteine; • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity; • aktivnost sa transferazom;
Ćelijska komponenta	• citosol; • Proteasom; • jedro; • citoplazma;
Biološki proces	• ubiquitin-dependent protein catabolic process; • prostate gland growth; • rhythmic process; • Proteoliza; • positive regulation of phosphatidylinositol 3-kinase signaling; • protein K48-linked ubiquitination; • GO:0022415 viral process; • brain development; • regulation of ubiquitin-dependent protein catabolic process; • ovarian follicle development; • sperm entry; • protein ubiquitination; • positive regulation of protein ubiquitination; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • protein autoubiquitination; • regulation of circadian rhythm; • androgen receptor signaling pathway; • response to progesterone; • progesterone receptor signaling pathway; • protein polyubiquitination; • proteasome-mediated ubiquitin-dependent protein catabolic process; • response to cocaine; • response to hydrogen peroxide; • negative regulation of dendritic spine morphogenesis; • cellular response to brain-derived neurotrophic factor stimulus;
	Izvori:Amigo / QuickGO
Ortolozi
	7337
	22215
	ENSG00000114062
	ENSMUSG00000025326
	Q05086
	O08759
NM_000462; NM_130838; NM_130839; NM_001354505; NM_001354506;
	NM_001354509; NM_001354512; NM_001354523; NM_001354526; NM_001354540; NM_001354541; NM_001354543; NM_001354545; NM_001354547; NM_001354549; NM_001354550; NM_001354507; NM_001354508; NM_001354511; NM_001354513; NM_001354538; NM_001354539; NM_001354542; NM_001354544; NM_001354546; NM_001354548; NM_001354551; NM_001374461
	NM_001033962; NM_011668; NM_173010
NP_000453; NP_570853; NP_570854; NP_001341434; NP_001341435;
	NP_001341438; NP_001341441; NP_001341452; NP_001341455; NP_001341469; NP_001341470; NP_001341472; NP_001341474; NP_001341476; NP_001341478; NP_001341479; NP_001341436; NP_001341437; NP_001341440; NP_001341442; NP_001341467; NP_001341468; NP_001341471; NP_001341473; NP_001341475; NP_001341477; NP_001341480; NP_001361390
NP_001029134; NP_035798; NP_001380595; NP_001380597; NP_001380598;
	NP_001380599; NP_001380600; NP_001380601; NP_766598; NP_001380902
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Ubikvitin-protein ligaza E3A (UBE3A), znana i kao E6AP ubikvitin-protein ligaza (E6AP) je enzim koji je kod ljudi kodiran genom UBE3A. Ovaj enzim je uključen u ciljanje proteina za razgradnju unutar ćelije.

Razgradnja proteina je normalan proces koji uklanja oštećene ili nepotrebne proteine i pomaže u održavanju normalnih funkcija ćelija. Ubikvitin proteinska ligaza E3A veže mali marker protein nazvan ubikvitin na proteine koji bi trebali biti razgrađeni. Ćelijske strukture zvane proteasomi prepoznaju i probavljaju proteine označene ubikvitinom.

Obje kopije gena UBE3A aktivne su u većini tjelesnih tkiva. U većini neurona, međutim, normalno je aktivna samo kopija naslijeđena od majke date osobe (majčina kopija); ovo je poznato kao očinsko utiskivanje. Noviji dokazi pokazuju da bar neke glijne ćelije i neuroni mogu ispoljavati bialelnu ekspresiju UBE3A.^[5]^[6] Zato je potreban dalji rad na ocrtavanju kompletne mape utiskivanja UBE3A kod ljudi i modelnih organizama, kao što su miševi.

Smatra se da se utišavanje Ube3a na očinskom alelu događa putem Ube3a-ATS dijela lincRNK zvan LNCAT (engleski: Large Non-Coding Antisense Transcript).^[7]

Gen UBE3A nalazi se na dugom (q) kraku hromosoma 15, između položaja 11 i 13, od baznog para 23,133.488 do baznog para 23,235.220.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 875 aminokiselina, a molekulska težina 100.688 Da.^[8]

10	20	30	40	50
MEKLHQCYWK	SGEPQSDDIE	ASRMKRAAAK	HLIERYYHQL	TEGCGNEACT
NEFCASCPTF	LRMDNNAAAI	KALELYKINA	KLCDPHPSKK	GASSAYLENS
KGAPNNSCSE	IKMNKKGARI	DFKDVTYLTE	EKVYEILELC	REREDYSPLI
RVIGRVFSSA	EALVQSFRKV	KQHTKEELKS	LQAKDEDKDE	DEKEKAACSA
AAMEEDSEAS	SSRIGDSSQG	DNNLQKLGPD	DVSVDIDAIR	RVYTRLLSNE
KIETAFLNAL	VYLSPNVECD	LTYHNVYSRD	PNYLNLFIIV	MENRNLHSPE
YLEMALPLFC	KAMSKLPLAA	QGKLIRLWSK	YNADQIRRMM	ETFQQLITYK
VISNEFNSRN	LVNDDDAIVA	ASKCLKMVYY	ANVVGGEVDT	NHNEEDDEEP
IPESSELTLQ	ELLGEERRNK	KGPRVDPLET	ELGVKTLDCR	KPLIPFEEFI
NEPLNEVLEM	DKDYTFFKVE	TENKFSFMTC	PFILNAVTKN	LGLYYDNRIR
MYSERRITVL	YSLVQGQQLN	PYLRLKVRRD	HIIDDALVRL	EMIAMENPAD
LKKQLYVEFE	GEQGVDEGGV	SKEFFQLVVE	EIFNPDIGMF	TYDESTKLFW
FNPSSFETEG	QFTLIGIVLG	LAIYNNCILD	VHFPMVVYRK	LMGKKGTFRD
LGDSHPVLYQ	SLKDLLEYEG	NVEDDMMITF	QISQTDLFGN	PMMYDLKENG
DKIPITNENR	KEFVNLYSDY	ILNKSVEKQF	KAFRRGFHMV	TNESPLKYLF
RPEEIELLIC	GSRNLDFQAL	EETTEYDGGY	TRDSVLIREF	WEIVHSFTDE
QKRLFLQFTT	GTDRAPVGGL	GKLKMIIAKN	GPDTERLPTS	HTCFNVLLLP
EYSSKEKLKE	RLLKAITYAK	GFGML

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

Klinički značaj

Mutacije unutar gena UBE3A odgovorne su za neke slučajeve Angelmanovog i Prader-Willijevog sindroma. Većina ovih mutacija rezultira abnormalno kratkom, nefunkcionalnom verzijom ubikvitin proteinske ligaze E3A. Budući da je kopija gena naslijeđena od oca osobe (očinska kopija) obično je neaktivna u mozgu, a mutacija u preostaloj majčinskoj kopiji sprečava stvaranje bilo kojeg enzima u mozgu. Ovaj gubitak funkcije enzima vjerovatno uzrokuje karakteristična obilježja ova dva stanja.

Gen UBE3A bnalazi se unutar ljudskog hromosomskog područja 15q11-13. Ostale abnormalnosti u ovoj regiji hromosoma 15 također mogu izazvati Angelmanov sindrom. Te hromosomske promjene uključuju delecije, preuređivanje (translokacije) genetičkog materijala i druge abnormalnosti. Poput mutacija unutar gena, ove hromosomske promjene sprečavaju stvaranje bilo koje funkcionalne ubikvitin-proteinske ligaze E3A u mozgu.

Interakcije

Pokazano je da UBE3A komjunicira sa:

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000114062 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000025326 - 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.
^ Jones KA, Han JE, DeBruyne JP, Philpot BD (juni 2016). "Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice". Scientific Reports. 6 (1): 28238. Bibcode:2016NatSR...628238J. doi:10.1038/srep28238. PMC 4910164. PMID 27306933.
^ Grier MD, Carson RP, Lagrange AH (20. 4. 2015). "Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells". PLOS ONE. 10 (4): e0124649. Bibcode:2015PLoSO..1024649G. doi:10.1371/journal.pone.0124649. PMC 4403805. PMID 25894543.
^ Runte M, Hüttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K (novembar 2001). "The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A". Human Molecular Genetics. 10 (23): 2687–700. doi:10.1093/hmg/10.23.2687. PMID 11726556.
^ "UniProt, Q05086". Pristupljeno 19. 7. 2021.
^ ^a ^b Oda H, Kumar S, Howley PM (august 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9557–62. Bibcode:1999PNAS...96.9557O. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.
^ Kühne C, Banks L (decembar 1998). "E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box". The Journal of Biological Chemistry. 273 (51): 34302–9. doi:10.1074/jbc.273.51.34302. PMID 9852095.
^ Kim S, Chahrour M, Ben-Shachar S, Lim J (juli 2013). "Ube3a/E6AP is involved in a subset of MeCP2 functions". Biochemical and Biophysical Research Communications. 437 (1): 67–73. doi:10.1016/j.bbrc.2013.06.036. PMID 23791832.
^ Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW (februar 1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Molecular and Cellular Biology. 19 (2): 1182–9. doi:10.1128/mcb.19.2.1182. PMC 116047. PMID 9891052.
^ Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y (august 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". The Journal of Biological Chemistry. 279 (34): 35664–70. doi:10.1074/jbc.M403385200. PMID 15175323.
^ Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y (mart 2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes to Cells. 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.
^ ^a ^b Nuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M (februar 1996). "Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5". The Journal of Biological Chemistry. 271 (5): 2795–800. doi:10.1074/jbc.271.5.2795. PMID 8576257.
^ Nuber U, Scheffner M (mart 1999). "Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction". The Journal of Biological Chemistry. 274 (11): 7576–82. doi:10.1074/jbc.274.11.7576. PMID 10066826.
^ ^a ^b Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M (novembar 1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes to Cells. 3 (11): 751–63. doi:10.1046/j.1365-2443.1998.00227.x. PMID 9990509. S2CID 1653536.
^ Hatakeyama S, Jensen JP, Weissman AM (juni 1997). "Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases". The Journal of Biological Chemistry. 272 (24): 15085–92. doi:10.1074/jbc.272.24.15085. PMID 9182527.
^ Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP (novembar 1999). "Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade". Science. 286 (5443): 1321–6. doi:10.1126/science.286.5443.1321. PMID 10558980.
^ ^a ^b Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (august 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Molecular Cell. 6 (2): 409–19. doi:10.1016/S1097-2765(00)00040-X. PMID 10983987.

Dopunska literatura

Bittel DC, Kibiryeva N, Talebizadeh Z, Driscoll DJ, Butler MG (januar 2005). "Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD". Genomics. 85 (1): 85–91. doi:10.1016/j.ygeno.2004.10.010. PMC 6800218. PMID 15607424.
Cassidy SB, Dykens E, Williams CA (2000). "Prader-Willi and Angelman syndromes: sister imprinted disorders". American Journal of Medical Genetics. 97 (2): 136–46. doi:10.1002/1096-8628(200022)97:2<136::AID-AJMG5>3.0.CO;2-V. PMID 11180221.
Clayton-Smith J, Laan L (februar 2003). "Angelman syndrome: a review of the clinical and genetic aspects". Journal of Medical Genetics. 40 (2): 87–95. doi:10.1136/jmg.40.2.87. PMC 1735357. PMID 12566516.
Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS, Christian SL, Kubota T, Halley DJ, Meijers-Heijboer H, Langlois S, Graham JM, Beuten J, Willems PJ, Ledbetter DH, Beaudet AL (januar 1999). "The spectrum of mutations in UBE3A causing Angelman syndrome" (PDF). Human Molecular Genetics. 8 (1): 129–35. doi:10.1093/hmg/8.1.129. PMID 9887341.
Moncla A, Malzac P, Livet MO, Voelckel MA, Mancini J, Delaroziere JC, Philip N, Mattei JF (juli 1999). "Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling". Journal of Medical Genetics. 36 (7): 554–60. doi:10.1136/jmg.36.7.554 (neaktivno 31. 5. 2021). PMC 1734398. PMID 10424818.CS1 održavanje: DOI nije aktivan od 2021 (link)
Williams CA (mart 2005). "Neurological aspects of the Angelman syndrome". Brain & Development. 27 (2): 88–94. doi:10.1016/j.braindev.2003.09.014. PMID 15668046. S2CID 11172742.

Vanjski linkovi

Šablon:Ligaza

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000114062 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000025326 - 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] Jones KA, Han JE, DeBruyne JP, Philpot BD (juni 2016). "Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice". Scientific Reports. 6 (1): 28238. Bibcode:2016NatSR...628238J. doi:10.1038/srep28238. PMC 4910164. PMID 27306933.

[6] Grier MD, Carson RP, Lagrange AH (20. 4. 2015). "Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells". PLOS ONE. 10 (4): e0124649. Bibcode:2015PLoSO..1024649G. doi:10.1371/journal.pone.0124649. PMC 4403805. PMID 25894543.

[Runte2001-7] Runte M, Hüttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K (novembar 2001). "The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A". Human Molecular Genetics. 10 (23): 2687–700. doi:10.1093/hmg/10.23.2687. PMID 11726556.

[UniProt-8] "UniProt, Q05086". Pristupljeno 19. 7. 2021.

[pmid10449731-9] Oda H, Kumar S, Howley PM (august 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9557–62. Bibcode:1999PNAS...96.9557O. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.

[pmid9852095-10] Kühne C, Banks L (decembar 1998). "E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box". The Journal of Biological Chemistry. 273 (51): 34302–9. doi:10.1074/jbc.273.51.34302. PMID 9852095.

[11] Kim S, Chahrour M, Ben-Shachar S, Lim J (juli 2013). "Ube3a/E6AP is involved in a subset of MeCP2 functions". Biochemical and Biophysical Research Communications. 437 (1): 67–73. doi:10.1016/j.bbrc.2013.06.036. PMID 23791832.

[pmid9891052-12] Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW (februar 1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Molecular and Cellular Biology. 19 (2): 1182–9. doi:10.1128/mcb.19.2.1182. PMC 116047. PMID 9891052.

[pmid15175323-13] Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y (august 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". The Journal of Biological Chemistry. 279 (34): 35664–70. doi:10.1074/jbc.M403385200. PMID 15175323.

[pmid18298802-14] Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y (mart 2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes to Cells. 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.

[pmid8576257-15] Nuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M (februar 1996). "Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5". The Journal of Biological Chemistry. 271 (5): 2795–800. doi:10.1074/jbc.271.5.2795. PMID 8576257.

[pmid10066826-16] Nuber U, Scheffner M (mart 1999). "Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction". The Journal of Biological Chemistry. 274 (11): 7576–82. doi:10.1074/jbc.274.11.7576. PMID 10066826.

[pmid9990509-17] Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M (novembar 1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes to Cells. 3 (11): 751–63. doi:10.1046/j.1365-2443.1998.00227.x. PMID 9990509. S2CID 1653536.

[pmid9182527-18] Hatakeyama S, Jensen JP, Weissman AM (juni 1997). "Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases". The Journal of Biological Chemistry. 272 (24): 15085–92. doi:10.1074/jbc.272.24.15085. PMID 9182527.

[pmid10558980-19] Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP (novembar 1999). "Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade". Science. 286 (5443): 1321–6. doi:10.1126/science.286.5443.1321. PMID 10558980.

[pmid10983987-20] Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (august 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Molecular Cell. 6 (2): 409–19. doi:10.1016/S1097-2765(00)00040-X. PMID 10983987.

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