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UniProtKB - P54252 (ATX3_HUMAN)

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Protein

Ataxin-3

Gene

ATXN3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates. Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins. Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. In response to misfolded substrate ubiquitination, mediates deubiquitination of monoubiquitinated STUB1/CHIP. Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription.4 Publications

Catalytic activityi

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei14Nucleophile1 Publication1
Active sitei119Proton acceptor2 Publications1
Active sitei1342 Publications1

GO - Molecular functioni

  • ATPase binding Source: ParkinsonsUK-UCL
  • identical protein binding Source: IntAct
  • Lys48-specific deubiquitinase activity Source: ParkinsonsUK-UCL
  • Lys63-specific deubiquitinase activity Source: ParkinsonsUK-UCL
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
  • thiol-dependent ubiquitinyl hydrolase activity Source: Reactome
  • ubiquitin protein ligase binding Source: ParkinsonsUK-UCL
Complete GO annotation...

GO - Biological processi

  • actin cytoskeleton organization Source: MGI
  • cellular response to heat Source: ParkinsonsUK-UCL
  • cellular response to misfolded protein Source: UniProtKB
  • chemical synaptic transmission Source: ProtInc
  • intermediate filament cytoskeleton organization Source: MGI
  • microtubule cytoskeleton organization Source: MGI
  • misfolded or incompletely synthesized protein catabolic process Source: UniProtKB
  • monoubiquitinated protein deubiquitination Source: UniProtKB
  • nervous system development Source: ProtInc
  • nucleotide-excision repair Source: ProtInc
  • positive regulation of ERAD pathway Source: ParkinsonsUK-UCL
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein deubiquitination Source: ParkinsonsUK-UCL
  • protein K48-linked deubiquitination Source: ParkinsonsUK-UCL
  • protein K63-linked deubiquitination Source: ParkinsonsUK-UCL
  • protein localization to cytosolic proteasome complex involved in ERAD pathway Source: ParkinsonsUK-UCL
  • regulation of cell-substrate adhesion Source: MGI
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW
  • ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processTranscription, Transcription regulation, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-5689877. Josephin domain DUBs.

Protein family/group databases

MEROPSiC86.001.

Names & Taxonomyi

Protein namesi
Recommended name:
Ataxin-3 (EC:3.4.19.12)
Alternative name(s):
Machado-Joseph disease protein 1
Spinocerebellar ataxia type 3 protein
Gene namesi
Name:ATXN3
Synonyms:ATX3, MJD, MJD1, SCA3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:7106. ATXN3.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: ProtInc
  • cytosol Source: ParkinsonsUK-UCL
  • mitochondrial matrix Source: ParkinsonsUK-UCL
  • mitochondrial membrane Source: ParkinsonsUK-UCL
  • nuclear inclusion body Source: ParkinsonsUK-UCL
  • nuclear matrix Source: UniProtKB-SubCell
  • nucleolus Source: HPA
  • nucleoplasm Source: Reactome
  • nucleus Source: ParkinsonsUK-UCL
  • plasma membrane Source: HPA
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Spinocerebellar ataxia 3 (SCA3)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSpinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA3 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. The molecular defect in SCA3 is the a CAG repeat expansion in ATX3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.
See also OMIM:109150

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi14C → A: Loss of deubiquitination activity. 2 Publications1
Mutagenesisi236S → A: Inhibits substrate trapping. 1 Publication1
Mutagenesisi256S → A: Inhibits substrate trapping. 1 Publication1
Mutagenesisi335S → A: No effect on ubiquitination. 1 Publication1

Keywords - Diseasei

Neurodegeneration, Spinocerebellar ataxia

Organism-specific databases

DisGeNETi4287.
MalaCardsiATXN3.
MIMi109150. phenotype.
OpenTargetsiENSG00000066427.
Orphaneti276238. Machado-Joseph disease type 1.
276241. Machado-Joseph disease type 2.
276244. Machado-Joseph disease type 3.
PharmGKBiPA134971833.

Polymorphism and mutation databases

BioMutaiATXN3.
DMDMi290457685.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000538311 – 364Ataxin-3Add BLAST364

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki1Peptide (Met-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki200Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei219PhosphoserineBy similarity1
Modified residuei265PhosphoserineCombined sources1
Modified residuei272PhosphoserineBy similarity1
Modified residuei328PhosphoserineBy similarity1

Post-translational modificationi

Monoubiquitinated N-terminally by UBE2W, possibly leading to activate the deubiquitinating enzyme activity.

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP54252.
PaxDbiP54252.
PeptideAtlasiP54252.
PRIDEiP54252.

PTM databases

iPTMnetiP54252.
PhosphoSitePlusiP54252.

Miscellaneous databases

PMAP-CutDBiA7LFZ5.

Expressioni

Tissue specificityi

Ubiquitous.

Gene expression databases

BgeeiENSG00000066427.
ExpressionAtlasiP54252. baseline and differential.
GenevisibleiP54252. HS.

Organism-specific databases

HPAiCAB021976.
HPA024123.
HPA069338.

Interactioni

Subunit structurei

Interacts with STUB1/CHIP (when monoubiquitinated) (By similarity). Interacts with DNA repair proteins RAD23A and RAD23B.By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

  • ATPase binding Source: ParkinsonsUK-UCL
  • identical protein binding Source: IntAct
  • ubiquitin protein ligase binding Source: ParkinsonsUK-UCL
Complete GO annotation...

Protein-protein interaction databases

BioGridi110433. 98 interactors.
IntActiP54252. 41 interactors.
MINTiMINT-272839.
STRINGi9606.ENSP00000376965.

Structurei

Secondary structure

1364
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi1 – 3Combined sources3
Helixi14 – 22Combined sources9
Beta strandi23 – 25Combined sources3
Helixi30 – 49Combined sources20
Turni53 – 55Combined sources3
Helixi56 – 62Combined sources7
Beta strandi70 – 73Combined sources4
Helixi78 – 85Combined sources8
Turni86 – 88Combined sources3
Beta strandi90 – 96Combined sources7
Turni97 – 100Combined sources4
Helixi106 – 108Combined sources3
Beta strandi109 – 116Combined sources8
Beta strandi119 – 126Combined sources8
Beta strandi129 – 134Combined sources6
Beta strandi141 – 143Combined sources3
Helixi145 – 158Combined sources14
Beta strandi161 – 167Combined sources7
Helixi173 – 176Combined sources4
Helixi178 – 180Combined sources3
Helixi222 – 240Combined sources19
Beta strandi243 – 245Combined sources3
Helixi246 – 257Combined sources12
Helixi279 – 282Combined sources4
Beta strandi287 – 289Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1YZBNMR-A1-182[»]
2AGANMR-A1-185[»]
2DOSNMR-A1-171[»]
2JRINMR-A1-182[»]
2KLZNMR-A222-263[»]
4WTHX-ray2.25A/B278-324[»]
4YS9X-ray2.00B278-324[»]
DisProtiDP00576.
ProteinModelPortaliP54252.
SMRiP54252.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP54252.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 180JosephinPROSITE-ProRule annotationAdd BLAST180
Domaini224 – 243UIM 1PROSITE-ProRule annotationAdd BLAST20
Domaini244 – 263UIM 2PROSITE-ProRule annotationAdd BLAST20
Domaini331 – 348UIM 3PROSITE-ProRule annotationAdd BLAST18

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi292 – 305Poly-GlnSequence analysisAdd BLAST14

Domaini

The UIM domains bind ubiquitin and interact with various E3 ubiquitin-protein ligase, such as STUB1/CHIP. They are essential to limit the length of ubiquitin chains (By similarity).By similarity

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG2935. Eukaryota.
ENOG4111G4B. LUCA.
GeneTreeiENSGT00390000001830.
HOVERGENiHBG025648.
InParanoidiP54252.
KOiK11863.
PhylomeDBiP54252.
TreeFamiTF314228.

Family and domain databases

Gene3Di1.25.40.10. 1 hit.
InterProiView protein in InterPro
IPR033865. Ataxin-3.
IPR006155. Josephin.
IPR011990. TPR-like_helical_dom.
IPR003903. UIM_dom.
PANTHERiPTHR14159. PTHR14159. 1 hit.
PfamiView protein in Pfam
PF02099. Josephin. 1 hit.
PF02809. UIM. 2 hits.
SMARTiView protein in SMART
SM01246. Josephin. 1 hit.
SM00726. UIM. 2 hits.
PROSITEiView protein in PROSITE
PS50957. JOSEPHIN. 1 hit.
PS50330. UIM. 2 hits.

Sequences (5)i

Sequence statusi: Complete.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P54252-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MESIFHEKQE GSLCAQHCLN NLLQGEYFSP VELSSIAHQL DEEERMRMAE 
        60         70         80         90        100
GGVTSEDYRT FLQQPSGNMD DSGFFSIQVI SNALKVWGLE LILFNSPEYQ 
       110        120        130        140        150
RLRIDPINER SFICNYKEHW FTVRKLGKQW FNLNSLLTGP ELISDTYLAL 
       160        170        180        190        200
FLAQLQQEGY SIFVVKGDLP DCEADQLLQM IRVQQMHRPK LIGEELAQLK 
       210        220        230        240        250
EQRVHKTDLE RVLEANDGSG MLDEDEEDLQ RALALSRQEI DMEDEEADLR 
       260        270        280        290        300
RAIQLSMQGS SRNISQDMTQ TSGTNLTSEE LRKRREAYFE KQQQKQQQQQ 
       310        320        330        340        350
QQQQQGDLSG QSSHPCERPA TSSGALGSDL GKACSPFIMF ATFTLYLTYE 
       360 
LHVIFALHYS SFPL
Length:364
Mass (Da):41,781
Last modified:March 2, 2010 - v4
Checksum:i4B2477EB67C30EFF
GO
Isoform 2 (identifier: P54252-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     332-364: KACSPFIMFATFTLYLTYELHVIFALHYSSFPL → DAMSEEDMLQAAVTMSLETVRNDLKTEGKK

Show »
Length:361
Mass (Da):41,250
Checksum:i90C3EF73BB26CAFD
GO
Isoform 3 (identifier: P54252-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     10-64: Missing.
     332-364: KACSPFIMFATFTLYLTYELHVIFALHYSSFPL → DAMSEEDMLQAAVTMSLETVRNDLKTEGKK

Show »
Length:306
Mass (Da):35,006
Checksum:iD2103044A948A525
GO
Isoform 4 (identifier: P54252-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     63-77: Missing.
     332-364: KACSPFIMFATFTLYLTYELHVIFALHYSSFPL → DAMSEEDMLQAAVTMSLETVRNDLKTEGKK

Note: Gene prediction based on EST data.
Show »
Length:346
Mass (Da):39,638
Checksum:iD4DE7B21BDE6C4F1
GO
Isoform 5 (identifier: P54252-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-179: Missing.
     332-364: KACSPFIMFATFTLYLTYELHVIFALHYSSFPL → DAMSEEDMLQAAVTMSLETVRNDLKTEGKK

Note: Gene prediction based on EST data.
Show »
Length:182
Mass (Da):20,633
Checksum:iF6BDA4CEE7251228
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti252A → T in AAB63352 (PubMed:9274833).Curated1
Sequence conflicti252A → T in AAB63353 (PubMed:9274833).Curated1
Sequence conflicti252A → T in AAB63354 (PubMed:9274833).Curated1

Polymorphismi

The poly-Gln region of ATXN3 is highly polymorphic (14 to 41 repeats) in the normal population and is expanded to about 55-82 repeats in spinocerebellar ataxia 3 (SCA3) patients.2 Publications
The MJD1a allele carries a single nucleotide substitution in codon 349 generating a stop codon instead of a Tyr. In the Japanese population, the MJD1a allele seems to be significantly associated with Gln expansion.3 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_013688212V → M3 PublicationsCorresponds to variant dbSNP:rs1048755Ensembl.1
Natural variantiVAR_013689306G → QQQQQQQQQQQQR3 Publications1
Natural variantiVAR_013690349 – 364Missing in allele MJD1a. 3 PublicationsAdd BLAST16

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0470851 – 179Missing in isoform 5. CuratedAdd BLAST179
Alternative sequenceiVSP_00278310 – 64Missing in isoform 3. CuratedAdd BLAST55
Alternative sequenceiVSP_04708663 – 77Missing in isoform 4. CuratedAdd BLAST15
Alternative sequenceiVSP_002784332 – 364KACSP…SSFPL → DAMSEEDMLQAAVTMSLETV RNDLKTEGKK in isoform 2, isoform 3, isoform 4 and isoform 5. 2 PublicationsAdd BLAST33

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S75313 mRNA. Translation: AAB33571.1.
U64820 mRNA. Translation: AAB63352.1.
U64821 mRNA. Translation: AAB63353.1.
U64822 mRNA. Translation: AAB63354.1.
AB050194 mRNA. Translation: BAB18798.1.
AB038653 Genomic DNA. Translation: BAB55645.1.
AB038653 Genomic DNA. Translation: BAB55646.1.
EU009923 Genomic DNA. Translation: ABS29269.1.
AL049872 Genomic DNA. No translation available.
AL121773 Genomic DNA. No translation available.
CH471061 Genomic DNA. Translation: EAW81472.1.
BC033711 mRNA. Translation: AAH33711.1.
CCDSiCCDS32143.1. [P54252-3]
CCDS45154.1. [P54252-4]
CCDS53908.1. [P54252-5]
CCDS9900.1. [P54252-2]
PIRiS50830.
RefSeqiNP_001121168.1. NM_001127696.1. [P54252-4]
NP_001158252.1. NM_001164780.1. [P54252-5]
NP_004984.2. NM_004993.5. [P54252-2]
NP_109376.1. NM_030660.4. [P54252-3]
UniGeneiHs.532632.

Genome annotation databases

EnsembliENST00000340660; ENSP00000339110; ENSG00000066427. [P54252-3]
ENST00000502250; ENSP00000425322; ENSG00000066427. [P54252-5]
ENST00000503767; ENSP00000426697; ENSG00000066427. [P54252-4]
ENST00000532032; ENSP00000437157; ENSG00000066427. [P54252-1]
ENST00000558190; ENSP00000478320; ENSG00000066427. [P54252-2]
GeneIDi4287.
KEGGihsa:4287.
UCSCiuc001yac.5. human. [P54252-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism, Triplet repeat expansion

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiATX3_HUMAN
AccessioniPrimary (citable) accession number: P54252
Secondary accession number(s): A7LFZ5
, D6RDL9, E9PB63, O15284, O15285, O15286, Q8N189, Q96TC3, Q96TC4, Q9H3N0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: March 2, 2010
Last modified: July 5, 2017
This is version 182 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references