ID   ATX3_RAT                Reviewed;         355 AA.
AC   O35815;
DT   28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1998, sequence version 1.
DT   24-JAN-2024, entry version 158.
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, Sca3;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC   TISSUE=Brain, and Testis;
RX   PubMed=10732811; DOI=10.1007/s100480050015;
RA   Schmitt I., Brattig T., Gossen M., Riess O.;
RT   "Characterization of the rat spinocerebellar ataxia type 3 gene.";
RL   Neurogenetics 1:103-112(1997).
RN   [2]
RP   CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-14; HIS-119 AND ASN-134, AND
RP   FUNCTION.
RX   PubMed=17696782; DOI=10.1515/bc.2007.107;
RA   Tzvetkov N., Breuer P.;
RT   "Josephin domain-containing proteins from a variety of species are active
RT   de-ubiquitination enzymes.";
RL   Biol. Chem. 388:973-978(2007).
RN   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22673903; DOI=10.1038/ncomms1871;
RA   Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA   Olsen J.V.;
RT   "Quantitative maps of protein phosphorylation sites across 14 different rat
RT   organs and tissues.";
RL   Nat. Commun. 3:876-876(2012).
RN   [4]
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 (PubMed:17696782). 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 (By similarity).
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 (By similarity). {ECO:0000250|UniProtKB:P54252,
CC       ECO:0000250|UniProtKB:Q9CVD2, ECO:0000269|PubMed:17696782}.
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:0000269|PubMed:17696782};
CC   -!- SUBUNIT: Interacts with STUB1/CHIP (when monoubiquitinated) (By
CC       similarity). Interacts with DNA repair proteins RAD23A and RAD23B.
CC       Interacts with BECN1 (via its poly-Gln domain) (By similarity).
CC       Interacts with PRKN, UBR2, VCP and tubulin (By similarity).
CC       {ECO:0000250|UniProtKB:P54252, ECO:0000250|UniProtKB:Q9CVD2}.
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   -!- TISSUE SPECIFICITY: Ubiquitously expressed (PubMed:10732811).
CC       {ECO:0000269|PubMed:10732811}.
CC   -!- DOMAIN: The UIM domains bind ubiquitin and interact with various E3
CC       ubiquitin-protein ligase, such as STUB1/CHIP (By similarity). They are
CC       essential to limit the length of ubiquitin chains (By similarity).
CC       {ECO:0000250|UniProtKB:Q9CVD2}.
CC   -!- PTM: Monoubiquitinated by UBE2W, possibly leading to activate the
CC       deubiquitinating enzyme activity (By similarity).
CC       {ECO:0000250|UniProtKB:P54252}.
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DR   EMBL; Y12319; CAA72986.1; -; mRNA.
DR   RefSeq; NP_067734.1; NM_021702.1.
DR   AlphaFoldDB; O35815; -.
DR   BMRB; O35815; -.
DR   SMR; O35815; -.
DR   BioGRID; 248780; 2.
DR   STRING; 10116.ENSRNOP00000007505; -.
DR   MEROPS; C86.001; -.
DR   iPTMnet; O35815; -.
DR   PhosphoSitePlus; O35815; -.
DR   jPOST; O35815; -.
DR   PaxDb; 10116-ENSRNOP00000007505; -.
DR   Ensembl; ENSRNOT00000007505.3; ENSRNOP00000007505.1; ENSRNOG00000005470.3.
DR   Ensembl; ENSRNOT00055024976; ENSRNOP00055020411; ENSRNOG00055014517.
DR   Ensembl; ENSRNOT00060007983; ENSRNOP00060005977; ENSRNOG00060004720.
DR   Ensembl; ENSRNOT00065025136; ENSRNOP00065019676; ENSRNOG00065015145.
DR   GeneID; 60331; -.
DR   KEGG; rno:60331; -.
DR   UCSC; RGD:621567; rat.
DR   AGR; RGD:621567; -.
DR   CTD; 4287; -.
DR   RGD; 621567; Atxn3.
DR   eggNOG; KOG2935; Eukaryota.
DR   GeneTree; ENSGT00390000001830; -.
DR   HOGENOM; CLU_031228_1_0_1; -.
DR   InParanoid; O35815; -.
DR   OrthoDB; 337428at2759; -.
DR   PhylomeDB; O35815; -.
DR   TreeFam; TF314228; -.
DR   Reactome; R-RNO-5689877; Josephin domain DUBs.
DR   Reactome; R-RNO-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR   PRO; PR:O35815; -.
DR   Proteomes; UP000002494; Chromosome 6.
DR   Bgee; ENSRNOG00000005470; Expressed in testis and 19 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR   GO; GO:0005759; C:mitochondrial matrix; ISO:RGD.
DR   GO; GO:0031966; C:mitochondrial membrane; ISO:RGD.
DR   GO; GO:0042405; C:nuclear inclusion body; ISO:RGD.
DR   GO; GO:0016363; C:nuclear matrix; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; ISO:RGD.
DR   GO; GO:0051117; F:ATPase binding; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISS:UniProtKB.
DR   GO; GO:0042826; F:histone deacetylase binding; IPI:RGD.
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; IDA:RGD.
DR   GO; GO:0001222; F:transcription corepressor binding; IPI:RGD.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; ISS: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; ISO:RGD.
DR   GO; GO:0071218; P:cellular response to misfolded protein; ISS:UniProtKB.
DR   GO; GO:0006338; P:chromatin remodeling; IEA:GOC.
DR   GO; GO:0035640; P:exploration behavior; ISO:RGD.
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; ISS:UniProtKB.
DR   GO; GO:1904262; P:negative regulation of TORC1 signaling; ISS:UniProtKB.
DR   GO; GO:1904294; P:positive regulation of ERAD pathway; ISO:RGD.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS: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:RGD.
DR   GO; GO:0036211; P:protein modification process; IDA:RGD.
DR   GO; GO:0006515; P:protein quality control for misfolded or incompletely synthesized proteins; ISS:UniProtKB.
DR   GO; GO:0010810; P:regulation of cell-substrate adhesion; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:RGD.
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; O35815; RN.
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_0000053833"
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..333
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..297
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        309..328
FT                   /note="Polar 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         268
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9CVD2"
FT   MOD_RES         272
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9CVD2"
FT   MOD_RES         273
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9CVD2"
FT   MOD_RES         321
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9CVD2"
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,S: Loss of enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:17696782"
FT   MUTAGEN         119
FT                   /note="H->A: Loss of enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:17696782"
FT   MUTAGEN         134
FT                   /note="N->A: Loss of enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:17696782"
SQ   SEQUENCE   355 AA;  40446 MW;  87B6A6EE54FF29F5 CRC64;
     MESIFHEKQE GSLCAQHCLN NLLQGEYFSP VELSSIAHQL DEEERLRMAE GGVTSEDYRT
     FLQQPSGNMD DSGFFSIQVI SNALKVWGLE LILFNSPEYQ RLRIDPINER SFICNYKEHW
     FTVRKLGKQW FNLNSLLTGP ELISDTYLAL FLAQLQQEGY SIFVVKGDLP DCEADQLLQM
     IKVQQMHRPK LIGEELAHLK EQSALKADLE RVLEAADGPG MFDDDEDDLQ RALAMSRQEI
     DMEDEEADLR RAIQLSMQGS SRGMCEDSPQ TSSTDLSSEE LRKRREAYFE KQQHQQQEAD
     RPGYLSYPCE RPTTSSGGLR SNQAGNAMSE EDVLRATVTV SLETAKDSLK AERKK
//