Ataxin-3 (ATXN3)

The protein contains 364 amino acids for an estimated molecular weight of 41781 Da.

 

Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:12297501, PubMed:17696782, PubMed:23625928, PubMed:28445460, PubMed:16118278). Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (PubMed:17696782). 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 (By similarity). Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription (PubMed:12297501). Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (PubMed:28445460). (updated: Jan. 31, 2018)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology.


Interpro domains
Total structural coverage: 52%
Model score: 29
MODL_I-TASSER-3.0

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VariantDescription
dbSNP:rs1048755

The reference OMIM entry for this protein is 109150

Machado-joseph disease; mjd
Spinocerebellar ataxia 3; sca3
Spinocerebellar atrophy iii
Azorean neurologic disease
Spinopontine atrophy
Nigrospinodentatal degeneration

A number sign (#) is used with this entry because Machado-Joseph disease (MJD), also known as spinocerebellar ataxia-3 (SCA3), is caused by a (CAG)n trinucleotide repeat expansion encoding glutamine repeats in the ataxin-3 gene (ATXN3; 607047). Normal individuals have up to 44 glutamine repeats, and MJD patients have between 52 and 86 glutamine repeats. Incomplete penetrance is associated with 45 to 51 repeats (Todd and Paulson, 2010). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

DESCRIPTION

Machado-Joseph disease, named for affected families of Azorean extraction, is an autosomal dominant progressive neurologic disorder characterized principally by ataxia, spasticity, and ocular movement abnormalities. Although independently described as a seemingly separate disorder, spinocerebellar ataxia-3 is now known to be the same as Machado-Joseph disease. Three classic clinical subtypes of MJD are recognized: type 1 with early onset and marked pyramidal and dystonic signs; type 2, or pure, with predominant cerebellar ataxia; and type 3 with later-onset and peripheral neuropathy (Franca et al., 2008).

CLINICAL FEATURES

- Early Descriptions, Diagnostic Uncertainties, and Geographic Distribution Among Portuguese immigrants living in New England, Nakano et al. (1972) described a form of dominantly inherited ataxia occurring in descendants of William Machado, a native of an island in the Portuguese Azores. The disorder began as ataxic gait after age 40. Six patients studied in detail showed abnormally large amounts of air in the posterior fossa on pneumoencephalogram, denervation atrophy of muscle, and diabetes mellitus. Other families of Azorean origin living in Massachusetts (Romanul et al., 1977; Woods and Schaumburg, 1972) and in California (Rosenberg et al., 1976) were reported. Romanul et al. (1977) suggested that all 4 reported kindreds had the same mutant gene despite differences in expression. The progressive neurologic disorder was characterized by gait ataxia, features similar to those in Parkinson disease (PD; 168600) in some patients, limitation of eye movements, widespread fasciculations of muscles, loss of reflexes in the lower limbs, followed by nystagmus, mild cerebellar tremors, and extensor plantar responses. Postmortem examinations showed loss of neurons and gliosis in the substantia nigra, nuclei pontis (and in the putamen in one case) as well as the nuclei of the vestibular and cranial nerves, columns of Clarke and anterior horns. Rosenberg (1977) referred to the disorder he and his colleagues described as Joseph disease (Rosenberg et al., 1976) and questioned that one can be certain of its identity to the disorder in other families of Azorean origin. In January 1976, Corino Andrade (Coutinho et al., 1977) 'went to the Azores...to investigate a degenerative disease of the central nervous system known to exist there. We saw 40 patients belonging to 15 families (in the islands of Flores and St. Michael)...It is our opinion that different families just mentioned, which have been taken as separate diseases, are only clinically diverse forms of the same disorder, of which symptomatic pleomorphism is a conspicuous feature.' In the same year, Romanul et al. (1977) arrived at the same conclusion. The full paper by Coutinho and Andrade (1978) appeared the next year. Lima and Coutinho (1980) described a mainland Portuguese family. The possibility that the Joseph family wa ... More on the omim web site

Subscribe to this protein entry history

Feb. 5, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 109150 was added.

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed