ID ATX3_MOUSE Reviewed; 355 AA. AC Q9CVD2; DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot. DT 28-FEB-2003, sequence version 2. DT 27-MAR-2024, entry version 172. DE RecName: Full=Ataxin-3; DE EC=3.4.19.12; DE AltName: Full=Machado-Joseph disease protein 1 homolog; GN Name=Atxn3; Synonyms=Mjd; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=NOD; TISSUE=Stomach, and Thymus; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [2] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic brain; RX PubMed=15345747; DOI=10.1074/mcp.m400085-mcp200; RA Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.; RT "Phosphoproteomic analysis of the developing mouse brain."; RL Mol. Cell. Proteomics 3:1093-1101(2004). RN [3] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268 AND SER-273, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [4] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219; SER-268; SER-272; RP SER-273 AND SER-321, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Brown adipose tissue, Heart, Kidney, Lung, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [5] RP FUNCTION, INTERACTION WITH STUB1, UBIQUITINATION, AND MUTAGENESIS OF RP CYS-14. RX PubMed=21855799; DOI=10.1016/j.molcel.2011.05.036; RA Scaglione K.M., Zavodszky E., Todi S.V., Patury S., Xu P., RA Rodriguez-Lebron E., Fischer S., Konen J., Djarmati A., Peng J., RA Gestwicki J.E., Paulson H.L.; RT "Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP."; RL Mol. Cell 43:599-612(2011). RN [6] RP INTERACTION WITH BECN1, FUNCTION, AND DOMAIN. RX PubMed=28445460; DOI=10.1038/nature22078; RA Ashkenazi A., Bento C.F., Ricketts T., Vicinanza M., Siddiqi F., Pavel M., RA Squitieri F., Hardenberg M.C., Imarisio S., Menzies F.M., Rubinsztein D.C.; RT "Polyglutamine tracts regulate beclin 1-dependent autophagy."; RL Nature 545:108-111(2017). RN [7] RP 3D-STRUCTURE MODELING. RX PubMed=12486728; DOI=10.1002/prot.10280; RA Albrecht M., Hoffmann D., Evert B.O., Schmitt I., Wuellner U., Lengauer T.; RT "Structural modeling of ataxin-3 reveals distant homology to adaptins."; RL Proteins 50:355-370(2003). CC -!- FUNCTION: Deubiquitinating enzyme involved in protein homeostasis CC maintenance, transcription, cytoskeleton regulation, myogenesis and CC degradation of misfolded chaperone substrates (By similarity). Binds CC long polyubiquitin chains and trims them, while it has weak or no CC activity against chains of 4 or less ubiquitins (By similarity). CC Involved in degradation of misfolded chaperone substrates via its CC interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, CC and restricts the length of ubiquitin chain attached to STUB1/CHIP CC substrates and preventing further chain extension (PubMed:21855799). CC Interacts with key regulators of transcription and represses CC transcription: acts as a histone-binding protein that regulates CC transcription (By similarity). Acts as a negative regulator of mTORC1 CC signaling in response to amino acid deprivation by mediating CC deubiquitination of RHEB, thereby promoting RHEB inactivation by the CC TSC-TBC complex (By similarity). Regulates autophagy via the CC deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of CC BECN1 (PubMed:28445460). {ECO:0000250|UniProtKB:P54252, CC ECO:0000269|PubMed:21855799, ECO:0000269|PubMed:28445460}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000305|PubMed:21855799, CC ECO:0000305|PubMed:28445460}; CC -!- SUBUNIT: Interacts with STUB1/CHIP (when monoubiquitinated) CC (PubMed:21855799). Interacts with DNA repair proteins RAD23A and RAD23B CC (By similarity). Interacts with BECN1 (via its poly-Gln domain) CC (PubMed:28445460). Interacts with PRKN, UBR2, VCP and tubulin (By CC similarity). {ECO:0000250|UniProtKB:P54252, CC ECO:0000269|PubMed:21855799, ECO:0000269|PubMed:28445460}. CC -!- SUBCELLULAR LOCATION: Nucleus matrix {ECO:0000250|UniProtKB:P54252}. CC Nucleus {ECO:0000250|UniProtKB:P54252}. Lysosome membrane CC {ECO:0000250|UniProtKB:P54252}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:P54252}. Note=Predominantly nuclear, but not CC exclusively, inner nuclear matrix. Recruited to lysosomal membrane in CC response to amino acid deprivation by the RagA/RRAGA-RagB/RRAGB CC complex. {ECO:0000250|UniProtKB:P54252}. CC -!- DOMAIN: The UIM domains bind ubiquitin and interact with various E3 CC ubiquitin-protein ligase, such as STUB1/CHIP. They are essential to CC limit the length of ubiquitin chains (PubMed:21855799). CC {ECO:0000269|PubMed:21855799}. CC -!- PTM: Monoubiquitinated by UBE2W, possibly leading to activate the CC deubiquitinating enzyme activity (By similarity). CC {ECO:0000250|UniProtKB:P54252}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK008675; BAB25825.3; -; mRNA. DR EMBL; AK030842; BAC27155.1; -; mRNA. DR CCDS; CCDS26115.1; -. DR RefSeq; NP_083981.2; NM_029705.3. DR AlphaFoldDB; Q9CVD2; -. DR BMRB; Q9CVD2; -. DR SMR; Q9CVD2; -. DR BioGRID; 225755; 17. DR IntAct; Q9CVD2; 2. DR MINT; Q9CVD2; -. DR STRING; 10090.ENSMUSP00000021606; -. DR MEROPS; C86.001; -. DR iPTMnet; Q9CVD2; -. DR PhosphoSitePlus; Q9CVD2; -. DR SwissPalm; Q9CVD2; -. DR EPD; Q9CVD2; -. DR MaxQB; Q9CVD2; -. DR PaxDb; 10090-ENSMUSP00000021606; -. DR ProteomicsDB; 277208; -. DR Pumba; Q9CVD2; -. DR Antibodypedia; 13668; 373 antibodies from 32 providers. DR DNASU; 110616; -. DR Ensembl; ENSMUST00000021606.12; ENSMUSP00000021606.6; ENSMUSG00000021189.12. DR GeneID; 110616; -. DR KEGG; mmu:110616; -. DR UCSC; uc007otv.2; mouse. DR AGR; MGI:1099442; -. DR CTD; 4287; -. DR MGI; MGI:1099442; Atxn3. DR VEuPathDB; HostDB:ENSMUSG00000021189; -. DR eggNOG; KOG2935; Eukaryota. DR GeneTree; ENSGT00390000001830; -. DR InParanoid; Q9CVD2; -. DR OMA; LGQAYIC; -. DR OrthoDB; 337428at2759; -. DR PhylomeDB; Q9CVD2; -. DR TreeFam; TF314228; -. DR BRENDA; 3.4.19.12; 3474. DR Reactome; R-MMU-5689877; Josephin domain DUBs. DR Reactome; R-MMU-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes. DR BioGRID-ORCS; 110616; 2 hits in 78 CRISPR screens. DR ChiTaRS; Atxn3; mouse. DR PRO; PR:Q9CVD2; -. DR Proteomes; UP000000589; Chromosome 12. DR RNAct; Q9CVD2; Protein. DR Bgee; ENSMUSG00000021189; Expressed in spermatid and 227 other cell types or tissues. DR ExpressionAtlas; Q9CVD2; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0005829; C:cytosol; ISS:ParkinsonsUK-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:Ensembl. DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:MGI. DR GO; GO:0031966; C:mitochondrial membrane; IDA:MGI. DR GO; GO:0042405; C:nuclear inclusion body; IDA:MGI. DR GO; GO:0016363; C:nuclear matrix; IEA:UniProtKB-SubCell. DR GO; GO:0005730; C:nucleolus; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:MGI. DR GO; GO:0005886; C:plasma membrane; ISO:MGI. DR GO; GO:0051117; F:ATPase binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0042826; F:histone deacetylase binding; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISS:ParkinsonsUK-UCL. DR GO; GO:1990380; F:K48-linked deubiquitinase activity; ISS:ParkinsonsUK-UCL. DR GO; GO:0061578; F:K63-linked deubiquitinase activity; ISS:ParkinsonsUK-UCL. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:MGI. DR GO; GO:0001222; F:transcription corepressor binding; ISO:MGI. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IMP:MGI. DR GO; GO:0071218; P:cellular response to misfolded protein; IMP:UniProtKB. DR GO; GO:0006338; P:chromatin remodeling; IEA:GOC. DR GO; GO:0035640; P:exploration behavior; IMP:MGI. DR GO; GO:0045104; P:intermediate filament cytoskeleton organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0000226; P:microtubule cytoskeleton organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0035520; P:monoubiquitinated protein deubiquitination; IDA:UniProtKB. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; ISS:UniProtKB. DR GO; GO:1904294; P:positive regulation of ERAD pathway; ISO:MGI. DR GO; GO:2000060; P:positive regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0071108; P:protein K48-linked deubiquitination; ISS:ParkinsonsUK-UCL. DR GO; GO:0070536; P:protein K63-linked deubiquitination; ISS:ParkinsonsUK-UCL. DR GO; GO:1904379; P:protein localization to cytosolic proteasome complex involved in ERAD pathway; ISO:MGI. DR GO; GO:0036211; P:protein modification process; ISO:MGI. DR GO; GO:0006515; P:protein quality control for misfolded or incompletely synthesized proteins; IMP:UniProtKB. DR GO; GO:0010810; P:regulation of cell-substrate adhesion; IMP:MGI. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:MGI. DR Gene3D; 3.90.70.40; -; 1. DR Gene3D; 1.10.287.10; S15/NS1, RNA-binding; 1. DR InterPro; IPR033865; Ataxin-3. DR InterPro; IPR006155; Josephin. DR InterPro; IPR003903; UIM_dom. DR PANTHER; PTHR14159; ATAXIN-3-RELATED; 1. DR PANTHER; PTHR14159:SF0; ATAXIN-3-RELATED; 1. DR Pfam; PF02099; Josephin; 1. DR Pfam; PF16619; SUIM_assoc; 1. DR Pfam; PF02809; UIM; 3. DR PRINTS; PR01233; JOSEPHIN. DR SMART; SM01246; Josephin; 1. DR SMART; SM00726; UIM; 3. DR PROSITE; PS50957; JOSEPHIN; 1. DR PROSITE; PS50330; UIM; 2. DR Genevisible; Q9CVD2; MM. PE 1: Evidence at protein level; KW Hydrolase; Isopeptide bond; Lysosome; Membrane; Nucleus; Phosphoprotein; KW Protease; Reference proteome; Repeat; Thiol protease; Transcription; KW Transcription regulation; Ubl conjugation; Ubl conjugation pathway. FT CHAIN 1..355 FT /note="Ataxin-3" FT /id="PRO_0000053832" FT DOMAIN 1..180 FT /note="Josephin" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331" FT DOMAIN 224..243 FT /note="UIM 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00213" FT DOMAIN 244..263 FT /note="UIM 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00213" FT DOMAIN 329..348 FT /note="UIM 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00213" FT REGION 257..355 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 257..276 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 277..291 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 14 FT /note="Nucleophile" FT /evidence="ECO:0000250|UniProtKB:P54252" FT ACT_SITE 119 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331" FT ACT_SITE 134 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331" FT MOD_RES 219 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:15345747, FT ECO:0007744|PubMed:21183079" FT MOD_RES 268 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" FT MOD_RES 272 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 273 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" FT MOD_RES 321 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT CROSSLNK 1 FT /note="Peptide (Met-Gly) (interchain with G-Cter in FT ubiquitin)" FT /evidence="ECO:0000250" FT CROSSLNK 200 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P54252" FT MUTAGEN 14 FT /note="C->A: Abolishes deubiquitinating activity." FT /evidence="ECO:0000269|PubMed:21855799" SQ SEQUENCE 355 AA; 40533 MW; D148DD10EA481D5B CRC64; MESIFHEKQE GSLCAQHCLN NLLQGEYFSP VELSSIAHQL DEEERLRMAE GGVTSEDYRT FLQQPSGNMD DSGFFSIQVI SNALKVWGLE LILFNSPEYQ RLRIDPINER SFICNYKEHW FTVRKLGKQW FNLNSLLTGP ELISDTYLAL FLAQLQQEGY SIFVVKGDLP DCEADQLLQM IKVQQMHRPK LIGEELAHLK EQSALKADLE RVLEAADGSG IFDEDEDDLQ RALAISRQEI DMEDEEADLR RAIQLSMQGS SRSMCENSPQ TSSPDLSSEE LRRRREAYFE KQQQQQQEVD RPGPLSYPRE RPTTSSGGRR SDQGGDAVSE EDMLRAAVTM SLETAKDNLK AERKK //