ID   ATX3L_HUMAN             Reviewed;         355 AA.
AC   Q9H3M9; B2RNY8;
DT   09-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT   09-JAN-2007, sequence version 2.
DT   24-JAN-2024, entry version 148.
DE   RecName: Full=Ataxin-3-like protein {ECO:0000305};
DE            EC=3.4.19.12 {ECO:0000269|PubMed:21118805, ECO:0000269|PubMed:26079537};
DE   AltName: Full=Machado-Joseph disease protein 1-like;
GN   Name=ATXN3L {ECO:0000312|HGNC:HGNC:24173}; Synonyms=ATX3L, MJDL;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15772651; DOI=10.1038/nature03440;
RA   Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA   Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA   Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA   Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA   Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA   Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA   Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA   Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA   Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA   Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA   Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA   Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA   Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA   Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA   Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA   Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA   Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA   Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA   Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA   Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA   Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA   Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA   Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA   Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA   Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA   Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA   Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA   Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA   Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA   Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA   McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA   Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA   Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA   Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA   Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA   Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA   Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA   Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA   Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA   Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA   d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA   Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA   Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA   Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA   Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA   Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA   Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA   Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA   Rogers J., Bentley D.R.;
RT   "The DNA sequence of the human X chromosome.";
RL   Nature 434:325-337(2005).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ASP-332.
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASP-332.
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 10-355, VARIANT ASP-332, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=11450850; DOI=10.1007/s100380170060;
RA   Ichikawa Y., Goto J., Hattori M., Toyoda A., Ishii K., Jeong S.-Y.,
RA   Hashida H., Masuda N., Ogata K., Kasai F., Hirai M., Maciel P.,
RA   Rouleau G.A., Sakaki Y., Kanazawa I.;
RT   "The genomic structure and expression of MJD, the Machado-Joseph disease
RT   gene.";
RL   J. Hum. Genet. 46:413-422(2001).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 1-190 IN COMPLEX WITH UBIQUITIN,
RP   FUNCTION, CATALYTIC ACTIVITY, AND ACTIVE SITE.
RX   PubMed=21118805; DOI=10.1074/jbc.m110.177360;
RA   Weeks S.D., Grasty K.C., Hernandez-Cuebas L., Loll P.J.;
RT   "Crystal structure of a Josephin-ubiquitin complex: evolutionary restraints
RT   on ataxin-3 deubiquitinating activity.";
RL   J. Biol. Chem. 286:4555-4565(2011).
RN   [6]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=26079537; DOI=10.18632/oncotarget.4128;
RA   Ge F., Chen W., Qin J., Zhou Z., Liu R., Liu L., Tan J., Zou T., Li H.,
RA   Ren G., Chen C.;
RT   "Ataxin-3 like (ATXN3L), a member of the Josephin family of
RT   deubiquitinating enzymes, promotes breast cancer proliferation by
RT   deubiquitinating Krueppel-like factor 5 (KLF5).";
RL   Oncotarget 6:21369-21378(2015).
CC   -!- FUNCTION: Deubiquitinating enzyme that cleaves both 'Lys-48'-linked and
CC       'Lys-63'-linked poly-ubiquitin chains (in vitro) (PubMed:21118805).
CC       Acts as a deubiquitinating enzyme for the transcription factor KLF5,
CC       playing a role in the regulation of KLF5 stability (PubMed:26079537).
CC       {ECO:0000269|PubMed:21118805, ECO:0000269|PubMed:26079537}.
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:21118805,
CC         ECO:0000269|PubMed:26079537};
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:11450850}.
CC   -!- MISCELLANEOUS: Identified only in primates. ATXN3L appeared to have
CC       arisen relatively recently, just prior to the first major division
CC       between hominids and old world monkeys. {ECO:0000305|PubMed:21118805}.
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DR   EMBL; AC004674; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471074; EAW98819.1; -; Genomic_DNA.
DR   EMBL; BC137186; AAI37187.1; -; mRNA.
DR   EMBL; BC137187; AAI37188.1; -; mRNA.
DR   EMBL; AB050195; BAB18799.1; -; mRNA.
DR   CCDS; CCDS48080.1; -.
DR   RefSeq; NP_001129467.1; NM_001135995.1.
DR   PDB; 3O65; X-ray; 2.70 A; A/C/E/G=1-190.
DR   PDBsum; 3O65; -.
DR   AlphaFoldDB; Q9H3M9; -.
DR   SMR; Q9H3M9; -.
DR   BioGRID; 124954; 11.
DR   IntAct; Q9H3M9; 2.
DR   STRING; 9606.ENSP00000369996; -.
DR   BindingDB; Q9H3M9; -.
DR   ChEMBL; CHEMBL4630855; -.
DR   MEROPS; C86.002; -.
DR   iPTMnet; Q9H3M9; -.
DR   PhosphoSitePlus; Q9H3M9; -.
DR   BioMuta; ATXN3L; -.
DR   DMDM; 122055954; -.
DR   MassIVE; Q9H3M9; -.
DR   PaxDb; 9606-ENSP00000369996; -.
DR   PeptideAtlas; Q9H3M9; -.
DR   ProteomicsDB; 80732; -.
DR   Antibodypedia; 23827; 63 antibodies from 16 providers.
DR   DNASU; 92552; -.
DR   Ensembl; ENST00000380622.5; ENSP00000369996.2; ENSG00000123594.7.
DR   GeneID; 92552; -.
DR   KEGG; hsa:92552; -.
DR   MANE-Select; ENST00000380622.5; ENSP00000369996.2; NM_001135995.2; NP_001129467.1.
DR   UCSC; uc010ned.4; human.
DR   AGR; HGNC:24173; -.
DR   CTD; 92552; -.
DR   DisGeNET; 92552; -.
DR   GeneCards; ATXN3L; -.
DR   HGNC; HGNC:24173; ATXN3L.
DR   HPA; ENSG00000123594; Tissue enriched (testis).
DR   MIM; 300920; gene.
DR   neXtProt; NX_Q9H3M9; -.
DR   OpenTargets; ENSG00000123594; -.
DR   PharmGKB; PA134884147; -.
DR   VEuPathDB; HostDB:ENSG00000123594; -.
DR   eggNOG; KOG2935; Eukaryota.
DR   GeneTree; ENSGT00390000001830; -.
DR   HOGENOM; CLU_031228_1_0_1; -.
DR   InParanoid; Q9H3M9; -.
DR   OMA; WGLEIIH; -.
DR   OrthoDB; 337428at2759; -.
DR   PhylomeDB; Q9H3M9; -.
DR   TreeFam; TF314228; -.
DR   PathwayCommons; Q9H3M9; -.
DR   Reactome; R-HSA-5689877; Josephin domain DUBs.
DR   SignaLink; Q9H3M9; -.
DR   BioGRID-ORCS; 92552; 10 hits in 768 CRISPR screens.
DR   GenomeRNAi; 92552; -.
DR   Pharos; Q9H3M9; Tbio.
DR   PRO; PR:Q9H3M9; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; Q9H3M9; Protein.
DR   Bgee; ENSG00000123594; Expressed in sperm and 18 other cell types or tissues.
DR   ExpressionAtlas; Q9H3M9; baseline and differential.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR   GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
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; 2.
DR   PRINTS; PR01233; JOSEPHIN.
DR   SMART; SM01246; Josephin; 1.
DR   SMART; SM00726; UIM; 2.
DR   PROSITE; PS50957; JOSEPHIN; 1.
DR   PROSITE; PS50330; UIM; 1.
DR   Genevisible; Q9H3M9; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Hydrolase; Nucleus; Protease; Reference proteome; Repeat;
KW   Thiol protease; Transcription; Transcription regulation;
KW   Ubl conjugation pathway.
FT   CHAIN           1..355
FT                   /note="Ataxin-3-like protein"
FT                   /id="PRO_0000271099"
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..258
FT                   /note="UIM 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00213"
FT   REGION          209..230
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          253..331
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        253..276
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        278..292
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        293..323
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        14
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000305|PubMed:21118805,
FT                   ECO:0007744|PDB:3O65"
FT   ACT_SITE        119
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000305|PubMed:21118805,
FT                   ECO:0007744|PDB:3O65"
FT   ACT_SITE        134
FT                   /evidence="ECO:0000305|PubMed:21118805,
FT                   ECO:0007744|PDB:3O65"
FT   VARIANT         266
FT                   /note="L -> F (in dbSNP:rs16999010)"
FT                   /id="VAR_029861"
FT   VARIANT         332
FT                   /note="G -> D (in dbSNP:rs4830842)"
FT                   /evidence="ECO:0000269|PubMed:11450850,
FT                   ECO:0000269|PubMed:15489334, ECO:0000269|Ref.2"
FT                   /id="VAR_029862"
FT   CONFLICT        101
FT                   /note="K -> M (in Ref. 4; BAB18799)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        314
FT                   /note="P -> A (in Ref. 4; BAB18799)"
FT                   /evidence="ECO:0000305"
FT   HELIX           14..23
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           30..48
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           49..51
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           56..62
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          67..69
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           77..85
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   TURN            86..88
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          90..93
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           97..101
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           106..108
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          111..118
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          120..126
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          129..132
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          137..139
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          141..143
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           145..152
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           153..156
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   STRAND          160..167
FT                   /evidence="ECO:0007829|PDB:3O65"
FT   HELIX           173..178
FT                   /evidence="ECO:0007829|PDB:3O65"
SQ   SEQUENCE   355 AA;  40747 MW;  EE5097A6E4476D75 CRC64;
     MDFIFHEKQE GFLCAQHCLN NLLQGEYFSP VELASIAHQL DEEERMRMAE GGVTSEEYLA
     FLQQPSENMD DTGFFSIQVI SNALKFWGLE IIHFNNPEYQ KLGIDPINER SFICNYKQHW
     FTIRKFGKHW FNLNSLLAGP ELISDTCLAN FLARLQQQAY SVFVVKGDLP DCEADQLLQI
     ISVEEMDTPK LNGKKLVKQK EHRVYKTVLE KVSEESDESG TSDQDEEDFQ RALELSRQET
     NREDEHLRST IELSMQGSSG NTSQDLPKTS CVTPASEQPK KIKEDYFEKH QQEQKQQQQQ
     SDLPGHSSYL HERPTTSSRA IESDLSDDIS EGTVQAAVDT ILEIMRKNLK IKGEK
//