ATX3_CAEEL
ID ATX3_CAEEL Reviewed; 317 AA.
AC O17850;
DT 28-MAR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Ataxin-3 homolog;
DE EC=3.4.19.12 {ECO:0000269|PubMed:17234717, ECO:0000269|PubMed:21317884};
DE AltName: Full=Machado-Joseph disease-like protein;
GN Name=atx-3; ORFNames=F28F8.6;
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239 {ECO:0000312|EMBL:CAB03016.1};
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2] {ECO:0000305}
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).
RN [3]
RP INTERACTION WITH NED-8.
RX PubMed=17935801; DOI=10.1016/j.bbamcr.2007.07.012;
RA Ferro A., Carvalho A.L., Teixeira-Castro A., Almeida C., Tome R.J.,
RA Cortes L., Rodrigues A.J., Logarinho E., Sequeiros J., Macedo-Ribeiro S.,
RA Maciel P.;
RT "NEDD8: a new ataxin-3 interactor.";
RL Biochim. Biophys. Acta 1773:1619-1627(2007).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF CYS-20;
RP SER-232 AND SER-260.
RX PubMed=17234717; DOI=10.1096/fj.06-7002com;
RA Rodrigues A.J., Coppola G., Santos C., Costa M.C., Ailion M., Sequeiros J.,
RA Geschwind D.H., Maciel P.;
RT "Functional genomics and biochemical characterization of the C. elegans
RT orthologue of the Machado-Joseph disease protein ataxin-3.";
RL FASEB J. 21:1126-1136(2007).
RN [5]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH CDC-48.1 AND UBXN-5, INTERACTION
RP WITH UBXN-5; CDC-48.1 AND CDC-48.2, AND DISRUPTION PHENOTYPE.
RX PubMed=19545544; DOI=10.1016/j.bbrc.2009.06.092;
RA Rodrigues A.J., Neves-Carvalho A., Ferro A., Rokka A., Corthals G.,
RA Logarinho E., Maciel P.;
RT "ATX-3, CDC-48 and UBXN-5: a new trimolecular complex in Caenorhabditis
RT elegans.";
RL Biochem. Biophys. Res. Commun. 386:575-581(2009).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN A COMPLEX WITH CDC-48.1 AND
RP UFD-2, INTERACTION WITH CDC-48.1 AND CDC-48.2, DISRUPTION PHENOTYPE, AND
RP MUTAGENESIS OF CYS-20 AND 296-ARG--ARG-299.
RX PubMed=21317884; DOI=10.1038/ncb2200;
RA Kuhlbrodt K., Janiesch P.C., Kevei E., Segref A., Barikbin R., Hoppe T.;
RT "The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and
RT proteostasis.";
RL Nat. Cell Biol. 13:273-281(2011).
RN [7]
RP SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=21526185; DOI=10.1371/journal.pone.0018512;
RA Rodrigues A.J., Neves-Carvalho A., Teixeira-Castro A., Rokka A.,
RA Corthals G., Logarinho E., Maciel P.;
RT "Absence of ataxin-3 leads to enhanced stress response in C. elegans.";
RL PLoS ONE 6:E18512-E18512(2011).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=27669035; DOI=10.1038/nsmb.3296;
RA Ackermann L., Schell M., Pokrzywa W., Kevei E., Gartner A., Schumacher B.,
RA Hoppe T.;
RT "E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break
RT repair and apoptosis.";
RL Nat. Struct. Mol. Biol. 23:995-1002(2016).
CC -!- FUNCTION: Acts as chain editing deubiquitinating enzyme that binds and
CC cleaves 'Lys-48'-linked polyubiquitin chains, with a preference for
CC chains containing four or more ubiquitin molecules thereby modulating
CC protein degradation by the ubiquitin-proteasome pathway
CC (PubMed:19545544, PubMed:17234717, PubMed:21317884). Probably by
CC regulating the IGF-1-insulin-like pathway, regulates lifespan
CC (PubMed:21317884). Regulates germline DNA double-strand-break repair
CC and apoptosis in response to DNA damage by recruiting E4 ubiquitin-
CC protein ligase ufd-2 to DNA repair foci (PubMed:27669035). Interacts
CC with key regulators of transcription and represses transcription (By
CC similarity). Acts as a histone-binding protein that regulates
CC transcription (By similarity). {ECO:0000250|UniProtKB:P54252,
CC ECO:0000269|PubMed:17234717, ECO:0000269|PubMed:19545544,
CC ECO:0000269|PubMed:21317884, ECO:0000269|PubMed:27669035}.
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:17234717,
CC ECO:0000269|PubMed:21317884};
CC -!- SUBUNIT: Forms a complex composed of deubiquitinating enzyme atx-3,
CC adapter ubxn-5 and cdc-48.1 (PubMed:19545544). Forms a complex composed
CC of deubiquitinating enzyme atx-3, E4 ubiquitin-protein ligase ufd-2 and
CC cdc-48.1 (PubMed:21317884). Interacts (via RRDR motif) with cdc-48.1
CC (via N-terminus) and cdc-48.2 (via N-terminus); the interaction with
CC cdc-48.1 is not required for atx-3 enzymatic activity (PubMed:19545544,
CC PubMed:21317884). Interacts (via C-terminus) with ubxn-5
CC (PubMed:19545544). May interact with ned-8 (PubMed:17935801).
CC {ECO:0000269|PubMed:17935801, ECO:0000269|PubMed:19545544,
CC ECO:0000269|PubMed:21317884}.
CC -!- INTERACTION:
CC O17850; P54812: cdc-48.2; NbExp=3; IntAct=EBI-320650, EBI-320265;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17234717,
CC ECO:0000269|PubMed:21526185}. Nucleus {ECO:0000269|PubMed:17234717,
CC ECO:0000269|PubMed:21526185}. Nucleus, nucleolus
CC {ECO:0000269|PubMed:27669035}. Note=Localizes predominantly in the
CC cytoplasm (PubMed:17234717). In the germline, following ionizing
CC radiation-induced DNA damage, localizes to foci within nucleoli where
CC it colocalizes with cdc-48.1 and/or cdc-48.2 and ufd-2, proteasome
CC alpha subunit and ubiquitinated proteins (PubMed:27669035).
CC {ECO:0000269|PubMed:17234717, ECO:0000269|PubMed:27669035}.
CC -!- TISSUE SPECIFICITY: Expressed in germline (at protein level)
CC (PubMed:27669035). Expressed in spermatheca, pharynx, dorsal and
CC ventral cords, some head neurons, hypodermis, body wall muscles and
CC coelomocytes (PubMed:17234717). {ECO:0000269|PubMed:17234717,
CC ECO:0000269|PubMed:27669035}.
CC -!- DEVELOPMENTAL STAGE: Expression begins during late embryogenesis and
CC continues in larvae and adults. {ECO:0000269|PubMed:17234717}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype (PubMed:17234717). In
CC response to ionizing radiation-mediated DNA damage, the number of
CC germline apoptotic corpses is increased, ufd-2 recruitment to nucleoli
CC foci is impaired, the number of ubiquitin foci is increased and rad-51
CC retention to DNA damage foci is reduced; the increased germline
CC apoptosis is suppressed in a ufd-2 (tm1380) mutant background
CC (PubMed:27669035). At the higher temperature of 25 degrees Celsius, 60
CC percent of animals are uncoordinated (PubMed:19545544). Shows
CC resistance to heat stress characterized by an increase in survival and
CC expression of heat shock proteins such as hsp-16.2 and hsp-4
CC (PubMed:21526185). Expression of genes involved in the ubiquitin-
CC proteasome pathway, motility, cell structure and signal transduction is
CC affected (PubMed:17234717). In a cdc-48.1 (tm544) mutant background,
CC causes a 50 percent increase in longevity, a delay in age-related
CC muscle degeneration and resistance to oxidative and heat stresses
CC (PubMed:21317884). In addition, induces dauer formation in 10 percent
CC of animals and increases gene transcription of several genes including
CC sod-3 and hsp-16.2 (PubMed:21317884). The overall levels of
CC polyubiquitinated proteins is not affected (PubMed:21317884). RNAi-
CC mediated knockdown of daf-16 abolishes the increase in lifespan
CC (PubMed:21317884). {ECO:0000269|PubMed:17234717,
CC ECO:0000269|PubMed:19545544, ECO:0000269|PubMed:21317884,
CC ECO:0000269|PubMed:21526185, ECO:0000269|PubMed:27669035}.
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DR EMBL; Z81071; CAB03016.1; -; Genomic_DNA.
DR PIR; T21511; T21511.
DR RefSeq; NP_506873.1; NM_074472.7.
DR AlphaFoldDB; O17850; -.
DR SMR; O17850; -.
DR BioGRID; 45043; 6.
DR DIP; DIP-27501N; -.
DR IntAct; O17850; 3.
DR STRING; 6239.F28F8.6.1; -.
DR MEROPS; C86.003; -.
DR iPTMnet; O17850; -.
DR EPD; O17850; -.
DR PaxDb; O17850; -.
DR PeptideAtlas; O17850; -.
DR EnsemblMetazoa; F28F8.6.1; F28F8.6.1; WBGene00006446.
DR EnsemblMetazoa; F28F8.6.2; F28F8.6.2; WBGene00006446.
DR EnsemblMetazoa; F28F8.6.3; F28F8.6.3; WBGene00006446.
DR UCSC; F28F8.6.1; c. elegans.
DR WormBase; F28F8.6; CE09760; WBGene00006446; atx-3.
DR eggNOG; KOG2935; Eukaryota.
DR GeneTree; ENSGT00390000001830; -.
DR HOGENOM; CLU_031228_1_1_1; -.
DR InParanoid; O17850; -.
DR OMA; IFHEKQQ; -.
DR OrthoDB; 1482722at2759; -.
DR PhylomeDB; O17850; -.
DR Reactome; R-CEL-5689877; Josephin domain DUBs.
DR Reactome; R-CEL-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR PRO; PR:O17850; -.
DR Proteomes; UP000001940; Chromosome V.
DR Bgee; WBGene00006446; Expressed in germ line (C elegans) and 4 other tissues.
DR GO; GO:0005737; C:cytoplasm; IDA:WormBase.
DR GO; GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:WormBase.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:WormBase.
DR GO; GO:0007268; P:chemical synaptic transmission; IMP:WormBase.
DR GO; GO:0016579; P:protein deubiquitination; IBA:GO_Central.
DR InterPro; IPR033865; Ataxin-3.
DR InterPro; IPR006155; Josephin.
DR InterPro; IPR003903; UIM_dom.
DR PANTHER; PTHR14159; PTHR14159; 1.
DR Pfam; PF02099; Josephin; 1.
DR Pfam; PF02809; UIM; 2.
DR SMART; SM01246; Josephin; 1.
DR PROSITE; PS50957; JOSEPHIN; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Hydrolase; Nucleus; Protease; Reference proteome; Repeat;
KW Thiol protease; Transcription; Transcription regulation;
KW Ubl conjugation pathway.
FT CHAIN 1..317
FT /note="Ataxin-3 homolog"
FT /id="PRO_0000053835"
FT DOMAIN 7..178
FT /note="Josephin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331"
FT DOMAIN 219..239
FT /note="UIM 1"
FT /evidence="ECO:0000305"
FT DOMAIN 247..264
FT /note="UIM 2"
FT /evidence="ECO:0000305"
FT REGION 254..317
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 296..299
FT /note="Interaction with cdc-48.1 and cdc-48.2"
FT /evidence="ECO:0000269|PubMed:21317884"
FT COMPBIAS 273..291
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 292..317
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 20
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331"
FT ACT_SITE 117
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331"
FT ACT_SITE 132
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00331"
FT MUTAGEN 20
FT /note="C->A: Loss of catalytic activity. In a cdc-48.1
FT (tm544) mutant background, causes an increase in longevity
FT and resistance to oxidative stress."
FT /evidence="ECO:0000269|PubMed:17234717,
FT ECO:0000269|PubMed:21317884"
FT MUTAGEN 232
FT /note="S->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:17234717"
FT MUTAGEN 260
FT /note="S->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:17234717"
FT MUTAGEN 296..299
FT /note="RRDR->HNHH: Loss of interaction with cdc-48.1 and
FT cdc-48.2."
FT /evidence="ECO:0000269|PubMed:21317884"
SQ SEQUENCE 317 AA; 35864 MW; 31798FD62667FB19 CRC64;
MSKDDPINSI FFEHQEAALC AQHALNMLLQ DALYKWQDLR DLAIQMDKME QQILGNANPT
PGRSENMNES GYFSIQVLEK ALETFSLKLT NIENPAMVDY KNNPLTARAY ICNLREHWFV
LRKFGNQWFE LNSVNRGPKL LSDTYVSMFL HQVSSEGYSI FVVQGVLPRS DADDLISLCP
VVPPKVTPKK EQKLEKVMTK FFNTVGKRLG GGSGAPPDSQ EEKDLAIAFA MSMETKDGSE
VSRSSAEIDE ENLRKAIELS QAPGPSEPAE IPLLTRSRSS TPPGASEPFS NAEQQRRDRQ
KFLERFEKKK EERNDEK
