Mammalian protein found in Homo sapiens
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Ataxin-7 (ATXN7) is a protein of the SCA7 gene, located on chromosome 3. It is a subunit of the SAGA chromatin remodeling complex, which regulates gene expression; it contains 892 amino acids with an expandable poly(Q) region close to the N-terminus.[4] The expandable poly(Q) motif region in the protein contributes crucially to spinocerebellar ataxia (SCA) pathogenesis by the induction of intranuclear inclusion bodies.[5] ATXN7 is associated with both olivopontocerebellar atrophy type 3 (OPCA3) and spinocerebellar ataxia type 7 (SCA7).
ATXN7 (yellow) and SPT20H (blue) in the large SAGA coactivator complex. SAGA has a size of 1.4-MDa and is a regulatory hub for gene expression, chromatin modification, and DNA damage repair and signaling.
Several CAG repeats within the coding region of the SCA genes will lead to pathological protein misfolding. The allele linked to SCA7 carries 37—306 CAG repeats near the N-terminus, whereas the normal allele has only 4—35 repeats.[6] The CAG repeats in the ATXN7 gene have been linked to cerebellar and brainstem degeneration as well as retinal conerod dystrophy. The polyglutamine (polyQ) expansion at the N-terminus causes protein aggregation, impairing the gene expression of photoreceptor cell survival, leading to the symptoms of ataxia and vision loss.[7] Research suggest that silencing of ATXN7 in the retina by RNAi can be a possible therapeutic strategy for patients with SCA7 retinal degeneration.[8]
The N-terminus of ATXN7 is attached to a structural scaffold protein in the SAGA complex, SUPT20H.[9] This interaction positions ATXN7 so that it can connect the deubiquitination (DUB) module to the complex, which is needed to remove ubiquitin modifications from histones, an essential step in transcription.[9][10] Without the interaction between an arginine (Arg531) on ATXN7's N-terminus and a serine (Ser182) on the SUPT20H protein, the DUB module would not be anchored to the SAGA complex correctly, leading to defects in histone deubiquitination and gene regulation.[9][10] Because of the length of the interaction being 3.3Å, it is characterized as a hydrogen bond keeping the two proteins attached.
SPT20H is able to keep ATXN7 attached to the core of the SAGA coactivator complex through this interaction between the Ser182 on SPT20H (blue) and the Arg531 on ATXN7 (yellow). This interaction can be characterized as a hydrogen bond.
Wolfe MS (18 April 2018). Wolfe MS (ed.). The molecular and cellular basis of neurodegenerative diseases: underlying mechanisms. Elsevier Science. ISBN978-0-12-811304-2. OCLC1040033113.
Helmlinger D, Hardy S, Eberlin A, Devys D, Tora L (2006). "Both normal and polyglutamine- expanded ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase- containing complexes". Biochemical Society Symposium. 73 (73): 155–163. doi:10.1042/bss0730155. PMID16626296.
Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY, etal. (April 2006). "Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-x(L)". Cellular Signalling. 18 (4): 541–552. doi:10.1016/j.cellsig.2005.05.024. PMID15964171.
Ansorge O, Giunti P, Michalik A, Van Broeckhoven C, Harding B, Wood N, etal. (September 2004). "Ataxin-7 aggregation and ubiquitination in infantile SCA7 with 180 CAG repeats". Annals of Neurology. 56 (3): 448–452. doi:10.1002/ana.20230. PMID15349877. S2CID8148133.
