| Structural highlights
Disease
[ATX1_HUMAN] Spinocerebellar ataxia type 1. Defects in ATXN1 are the cause of spinocerebellar ataxia type 1 (SCA1) [MIM:164400]; also known as olivopontocerebellar atrophy I (OPCA I or OPCA1). 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 cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA1 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. SCA1 is caused by expansion of a CAG repeat in the coding region of ATXN1. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.[1] [2]
Function
[ATX1_HUMAN] Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism. The expansion of the polyglutamine tract may alter this function.[3]
Publication Abstract from PubMed
Ataxin-1 is a human protein responsible for spinocerebellar ataxia type 1, a hereditary disease associated with protein aggregation and misfolding. Essential for ataxin-1 aggregation is the anomalous expansion of a polyglutamine tract near the protein N-terminus, but the sequence-wise distant AXH domain modulates and contributes to the process. The AXH domain is also involved in the nonpathologic functions of the protein, including a variety of intermolecular interactions with other cellular partners. The domain forms a globular dimer in solution and displays a dimer of dimers arrangement in the crystal asymmetric unit. Here, we have characterized the domain further by studying its behavior in the crystal and in solution. We solved two new structures of the domain crystallized under different conditions that confirm an inherent plasticity of the AXH fold. In solution, the domain is present as a complex equilibrium mixture of monomeric, dimeric, and higher molecular weight species. This behavior, together with the tendency of the AXH fold to be trapped in local conformations, and the multiplicity of protomer interfaces, makes the AXH domain an unusual example of a chameleon protein whose properties bear potential relevance for the aggregation properties of ataxin-1 and thus for disease.
Self-Assembly and Conformational Heterogeneity of the AXH Domain of Ataxin-1: An Unusual Example of a Chameleon Fold.,de Chiara C, Rees M, Menon RP, Pauwels K, Lawrence C, Konarev PV, Svergun DI, Martin SR, Chen YW, Pastore A Biophys J. 2013 Mar 19;104(6):1304-13. doi: 10.1016/j.bpj.2013.01.048. Epub 2013 , Mar 19. PMID:23528090[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Banfi S, Servadio A, Chung MY, Kwiatkowski TJ Jr, McCall AE, Duvick LA, Shen Y, Roth EJ, Orr HT, Zoghbi HY. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet. 1994 Aug;7(4):513-20. PMID:7951322 doi:http://dx.doi.org/10.1038/ng0894-513
- ↑ Quan F, Janas J, Popovich BW. A novel CAG repeat configuration in the SCA1 gene: implications for the molecular diagnostics of spinocerebellar ataxia type 1. Hum Mol Genet. 1995 Dec;4(12):2411-3. PMID:8634720
- ↑ Tong X, Gui H, Jin F, Heck BW, Lin P, Ma J, Fondell JD, Tsai CC. Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway. EMBO Rep. 2011 May;12(5):428-35. doi: 10.1038/embor.2011.49. Epub 2011 Apr 8. PMID:21475249 doi:10.1038/embor.2011.49
- ↑ de Chiara C, Rees M, Menon RP, Pauwels K, Lawrence C, Konarev PV, Svergun DI, Martin SR, Chen YW, Pastore A. Self-Assembly and Conformational Heterogeneity of the AXH Domain of Ataxin-1: An Unusual Example of a Chameleon Fold. Biophys J. 2013 Mar 19;104(6):1304-13. doi: 10.1016/j.bpj.2013.01.048. Epub 2013 , Mar 19. PMID:23528090 doi:http://dx.doi.org/10.1016/j.bpj.2013.01.048
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