[ATX3_HUMAN] Defects in ATXN3 are the cause of spinocerebellar ataxia type 3 (SCA3) [MIM:109150]; also known as Machado-Joseph disease (MJD). Spinocerebellar 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 degeneration of the cerebellum 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 ATXN3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.
[ATX3_HUMAN] 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.
The Josephin domain plays an important role in the cellular functions of ataxin-3, the protein responsible for the neurodegenerative Machado-Joseph disease. We have determined the solution structure of Josephin and shown that it belongs to the family of papain-like cysteine proteases, sharing the highest degree of structural similarity with bacterial staphopain. A currently unique structural feature of Josephin is a flexible helical hairpin formed by a 32-residue insertion, which could determine substrate specificity. By using the Josephin structure and the availability of NMR chemical shift assignments, we have mapped the enzyme active site by using the typical cysteine protease inhibitors, transepoxysuccinyl-L-eucylamido-4-guanidino-butane (E-64) and [L-3-trans-(propylcarbamyl)oxirane-2-carbonyl]-L-isoleucyl-L-proline (CA-074). We also demonstrate that the specific interaction of Josephin with the ubiquitin-like domain of the ubiquitin- and proteasome-binding factor HHR23B involves complementary exposed hydrophobic surfaces. The structural similarity with other deubiquitinating enzymes suggests a model for the proteolytic enzymatic activity of ataxin-3.
The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition.,Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10493-8. Epub 2005 Jul 14. PMID:16020535
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↑ Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, et al.. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov;8(3):221-8. PMID:7874163 doi:http://dx.doi.org/10.1038/ng1194-221
↑ Li F, Macfarlan T, Pittman RN, Chakravarti D. Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem. 2002 Nov 22;277(47):45004-12. Epub 2002 Sep 23. PMID:12297501 doi:10.1074/jbc.M205259200
↑ Tzvetkov N, Breuer P. Josephin domain-containing proteins from a variety of species are active de-ubiquitination enzymes. Biol Chem. 2007 Sep;388(9):973-8. PMID:17696782 doi:10.1515/BC.2007.107
↑ Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De Camilli P. Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12700-5. Epub 2005 Aug 23. PMID:16118278
↑ Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A. The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10493-8. Epub 2005 Jul 14. PMID:16020535