ATXN3

ATXN3
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1YZB, 2AGA, 2DOS, 2JRI, 2KLZ, 4WTH, 4YS9
Identifikatori
Aliasi	ATXN3
Vanjski ID-jevi	OMIM: 607047 MGI: 1099442 HomoloGene: 3658 GeneCards: ATXN3
Lokacija gena (čovjek) Hrom. Hromosom 14 (čovjek)[1] Bend 14q32.12 Početak 92,044,496 bp[1] Kraj 92,106,621 bp[1]
Lokacija gena (miš) Hrom. Hromosom 12 (miš)[2] Bend 12|12 E Početak 101,918,901 bp[2] Kraj 101,958,246 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • Lys63-specific deubiquitinase activity • cysteine-type peptidase activity • ATPase binding • Lys48-specific deubiquitinase activity • GO:0070122 peptidase activity • GO:0001948, GO:0016582 vezivanje za proteine • vezivanje identičnih proteina • hydrolase activity • thiol-dependent deubiquitinase • ubiquitin protein ligase binding • histone deacetylase activity Ćelijska komponenta • endoplasmic reticulum membrane • nuclear matrix • nukleoplazma • jedro • Jedarce • citosol • ćelijska membrana • citoplazma • mitochondrial matrix • mitochondrial membranes • nuclear inclusion body Biološki proces • Popravak ekscizijom nukleotida • GO:0009373 regulation of transcription, DNA-templated • protein K48-linked deubiquitination • positive regulation of ERAD pathway • transcription, DNA-templated • nervous system development • Proteoliza • protein K63-linked deubiquitination • intermediate filament cytoskeleton organization • protein localization to cytosolic proteasome complex involved in ERAD pathway • microtubule cytoskeleton organization • actin cytoskeleton organization • chemical synaptic transmission • protein deubiquitination • ubiquitin-dependent protein catabolic process • protein quality control for misfolded or incompletely synthesized proteins • regulation of cell-substrate adhesion • cellular response to heat • monoubiquitinated protein deubiquitination • proteasome-mediated ubiquitin-dependent protein catabolic process • cellular response to misfolded protein • exploration behavior • histone H3 deacetylation Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	4287	110616
Ensembl	ENSG00000066427	ENSMUSG00000021189
UniProt	P54252 Q4VBR4	Q9CVD2
RefSeq (mRNK)	NM_001024631 NM_001127696 NM_001127697 NM_001164774 NM_001164776 NM_001164777 NM_001164778 NM_001164779 NM_001164780 NM_001164781 NM_001164782 NM_004993 NM_030660	NM_001167914 NM_029705
RefSeq (bjelančevina)	NP_001121168 NP_001121169 NP_001158246 NP_001158248 NP_001158249 NP_001158250 NP_001158251 NP_001158252 NP_001158253 NP_001158254 NP_004984 NP_109376	NP_001161386 NP_083981
Lokacija (UCSC)	Chr 14: 92.04 – 92.11 Mb	Chr 12: 101.92 – 101.96 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Ataksin-3 je protein koji je kod ljudi kodiran genom ATXN3.^[5][6]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 364 aminokiseline, a molekulska težina 41 781 Da.^[7]

10		20		30		40		50
MESIFHEKQE		GSLCAQHCLN		NLLQGEYFSP		VELSSIAHQL		DEEERMRMAE
GGVTSEDYRT		FLQQPSGNMD		DSGFFSIQVI		SNALKVWGLE		LILFNSPEYQ
RLRIDPINER		SFICNYKEHW		FTVRKLGKQW		FNLNSLLTGP		ELISDTYLAL
FLAQLQQEGY		SIFVVKGDLP		DCEADQLLQM		IRVQQMHRPK		LIGEELAQLK
EQRVHKTDLE		RVLEANDGSG		MLDEDEEDLQ		RALALSRQEI		DMEDEEADLR
RAIQLSMQGS		SRNISQDMTQ		TSGTNLTSEE		LRKRREAYFE		KQQQKQQQQQ
QQQQQGDLSG		QSSHPCERPA		TSSGALGSDL		GKACSPFIMF		ATFTLYLTYE
LHVIFALHYS		SFPL

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

Machado-Josephova bolest, poznata i kao spinocerebelarna ataksija-3, autosomno je dominantan neurvni poremećaj. Protein kodiran genom ATXN3 sadrži (CAG) n ponavljanja u kodirajućem području, a širenje tih ponavljanja sa normalnih 13-36 na 68-79 uzrok je Machado-Josephove bolesti. Postoji inverzna korelacija između starosti i broja ponovljenih CAG. Za ovaj gen su opisane alternativno prerađene varijante transkripta koje kodiraju različite izoforme.^[6]

Interakcije

Pokazano je da ataksin 3 komunicira sa:

• RAD23A,^[8]
• RAD23B,^[8] i
• VCP.^[9][10]

Modelni organizmi

U proučavanju PNPO funkcije, korišteni su modelni organizmi. Uvjetna linija nokaut-miševa, zvana Atxn3,^[11][12] generirana je kao dio programa Međunarosnog konzorcija za miševe – visokopropusnog projekta mutageneze za generiranje i distribuciju životinjskih modela bolesti zainteresiranim naučnicima.^[13][14][15]

Muške i ženske životinje prolazile su standardizirani fenotipski skrining, kako bi se utvrdili efekti delecije.

Fenotip Atxn3 nokaut-miša

Svojstvo	Fenotip
Vijabilnost homozigota	Normalno
Studija recesivne letalnosti	Normalno
Plodnost	Normalno
Tjelesna težina	Normalno
Test otvorenog polja: anksioznost	Normalno
Neurološka procjena	Normalno
Snaga stiska	Normalno
Test vruće ploče	Normalno
Dismorfologija	Normalno
Indirektna kalorimetrija	Normalno
Test tolerancije glukoze	Normalno
Slušni odgovor moždanog stabla	Normalno
DEXA	Normalno
Insulin	Normalno
Radiografija	Normalno
Tjelesna temperatura	Normalno
Morfologija oka	Normalno
Klinička hemija (nalaz)	Normalno
Plazmatski imunoglobulini	Normalno
Hematologija	Normalno
Leukociti periferne krvi	Normalno
Mikronukleus test	Normalno
Težina srca	Normalno
Histopatologija oka	Normalno
Salmonella infekcija	Normal[16]
Citrobacter infekcija	Normal[17]
Svi testovi i analize su iz [18][19]

Reference

1. GRCh38: Ensembl release 89: ENSG00000066427 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021189 - 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. Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S (Jul 1993). "The gene for Machado-Joseph disease maps to human chromosome 14q". Nature Genetics. 4 (3): 300–4. doi:10.1038/ng0793-300. PMID 8358439. S2CID 27424416.
6. "Entrez Gene: ATXN3 ataxin 3".
7. "UniProt, P54252". Pristupljeno 21. 7. 2021.
8. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (Jul 2000). "Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B". Human Molecular Genetics. 9 (12): 1795–803. doi:10.1093/hmg/9.12.1795. PMID 10915768.
9. Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K (Sep 2003). "Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis". Molecular and Cellular Biology. 23 (18): 6469–83. doi:10.1128/MCB.23.18.6469-6483.2003. PMC 193705. PMID 12944474.
10. Wang Q, Li L, Ye Y (Mar 2008). "Inhibition of p97-dependent protein degradation by Eeyarestatin I". The Journal of Biological Chemistry. 283 (12): 7445–54. doi:10.1074/jbc.M708347200. PMC 2276333. PMID 18199748.
11. "International Knockout Mouse Consortium". Arhivirano s originala, 3. 4. 2012. Pristupljeno 21. 7. 2021.
12. "Mouse Genome Informatics".
13. Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
14. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
15. Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
16. "Salmonella infection data for Pnpo". Wellcome Trust Sanger Institute.
17. "Citrobacter infection data for Pnpo". Wellcome Trust Sanger Institute.
18. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
19. Mouse Resources Portal, Wellcome Trust Sanger Institute.

Dopunska literatura

• Goto J, Watanabe M, Ichikawa Y, Yee SB, Ihara N, Endo K, Igarashi S, Takiyama Y, Gaspar C, Maciel P, Tsuji S, Rouleau GA, Kanazawa I (Aug 1997). "Machado-Joseph disease gene products carrying different carboxyl termini". Neuroscience Research. 28 (4): 373–7. doi:10.1016/S0168-0102(97)00056-4. PMID 9274833. S2CID 27241785.
• Schöls L, Vieira-Saecker AM, Schöls S, Przuntek H, Epplen JT, Riess O (Jun 1995). "Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients". Human Molecular Genetics. 4 (6): 1001–5. doi:10.1093/hmg/4.6.1001. PMID 7655453.
• Stevanin G, Cancel G, Dürr A, Chneiweiss H, Dubourg O, Weissenbach J, Cann HM, Agid Y, Brice A (Jan 1995). "The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2". American Journal of Human Genetics. 56 (1): 193–201. PMC 1801316. PMID 7825578.
• Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I (Nov 1994). "CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1". Nature Genetics. 8 (3): 221–8. doi:10.1038/ng1194-221. PMID 7874163. S2CID 29188685.
• Maruyama K, Sugano S (Jan 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.
• Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A (Jun 1996). "Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo". Nature Genetics. 13 (2): 196–202. doi:10.1038/ng0696-196. PMID 8640226. S2CID 21966287.
• Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck KH, Pittman RN (Apr 1997). "Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain". Annals of Neurology. 41 (4): 453–62. doi:10.1002/ana.410410408. PMID 9124802. S2CID 43460483.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR (Apr 1998). "Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract". The Journal of Biological Chemistry. 273 (15): 9158–67. doi:10.1074/jbc.273.15.9158. PMID 9535906.
• Tait D, Riccio M, Sittler A, Scherzinger E, Santi S, Ognibene A, Maraldi NM, Lehrach H, Wanker EE (Jun 1998). "Ataxin-3 is transported into the nucleus and associates with the nuclear matrix". Human Molecular Genetics. 7 (6): 991–7. doi:10.1093/hmg/7.6.991. PMID 9580663.
• Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (Jul 2000). "Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B". Human Molecular Genetics. 9 (12): 1795–803. doi:10.1093/hmg/9.12.1795. PMID 10915768.
• Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, Hashida H, Masuda N, Ogata K, Kasai F, Hirai M, Maciel P, Rouleau GA, Sakaki Y, Kanazawa I (2001). "The genomic structure and expression of MJD, the Machado-Joseph disease gene". Journal of Human Genetics. 46 (7): 413–22. doi:10.1007/s100380170060. PMID 11450850.
• Chai Y, Shao J, Miller VM, Williams A, Paulson HL (Jul 2002). "Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis". Proceedings of the National Academy of Sciences of the United States of America. 99 (14): 9310–5. Bibcode:2002PNAS...99.9310C. doi:10.1073/pnas.152101299. PMC 123137. PMID 12084819.
• Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (Jul 2002). "Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch". Neurobiology of Disease. 10 (2): 88–99. doi:10.1006/nbdi.2002.0502. PMID 12127147. S2CID 25183307.
• Li F, Macfarlan T, Pittman RN, Chakravarti D (Nov 2002). "Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities". The Journal of Biological Chemistry. 277 (47): 45004–12. doi:10.1074/jbc.M205259200. PMID 12297501.
• Albrecht M, Hoffmann D, Evert BO, Schmitt I, Wüllner U, Lengauer T (Feb 2003). "Structural modeling of ataxin-3 reveals distant homology to adaptins". Proteins. 50 (2): 355–70. doi:10.1002/prot.10280. PMID 12486728.
• Marchal S, Shehi E, Harricane MC, Fusi P, Heitz F, Tortora P, Lange R (Aug 2003). "Structural instability and fibrillar aggregation of non-expanded human ataxin-3 revealed under high pressure and temperature". The Journal of Biological Chemistry. 278 (34): 31554–63. doi:10.1074/jbc.M304205200. PMID 12766160.

Vanjski linkovi

• GeneReviews/NCBI/NIH/UW entry on Spinocerebellar Ataxia Type 3
• Lokacija ljudskog genoma ATXN3 i stranica sa detaljima o genu ATXN3 u UCSC Genome Browseru.