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)
Kraj	92,106,621 bp
Lokacija gena (miš)
Hrom.	Hromosom 12 (miš)
Kraj	101,958,246 bp
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
	4287
	110616
	ENSG00000066427
	ENSMUSG00000021189
	P54252; Q4VBR4
	Q9CVD2
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
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
	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:

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

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000066427 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021189 - 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.
^ 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.
^ ^a ^b "Entrez Gene: ATXN3 ataxin 3".
^ "UniProt, P54252". Pristupljeno 21. 7. 2021.
^ ^a ^b 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.
^ 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.
^ 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.
^ "International Knockout Mouse Consortium". Arhivirano s originala, 3. 4. 2012. Pristupljeno 21. 7. 2021.
^ "Mouse Genome Informatics".
^ 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.
^ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
^ 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.
^ "Salmonella infection data for Pnpo". Wellcome Trust Sanger Institute.
^ "Citrobacter infection data for Pnpo". Wellcome Trust Sanger Institute.
^ 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.
^ 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.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000066427 - Ensembl, maj 2017

[refGRCm38Ensembl-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.

[pmid8358439-5] 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.

[EntrezGene-6] "Entrez Gene: ATXN3 ataxin 3".

[UniProt-7] "UniProt, P54252". Pristupljeno 21. 7. 2021.

[pmid10915768-8] 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.

[pmid12944474-9] 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.

[pmid18199748-10] 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.

[allele_ref-11] "International Knockout Mouse Consortium". Arhivirano s originala, 3. 4. 2012. Pristupljeno 21. 7. 2021.

[mgi_allele_ref-12] "Mouse Genome Informatics".

[pmid21677750-13] 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.

[mouse_library-14] Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.

[mouse_for_all_reasons-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.

[''Salmonella''_infection-16] "Salmonella infection data for Pnpo". Wellcome Trust Sanger Institute.

[''Citrobacter''_infection-17] "Citrobacter infection data for Pnpo". Wellcome Trust Sanger Institute.

[mgp_reference-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.

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