Biology:Ataxin 7
| Ataxin-7 | |
|---|---|
 Ataxin-7 is a protein within the SAGA chromatin remodeling complex. It acts as a transcription factor that regulates gene expression. The N-terminus is shown at the bottom. | |
| Identifiers | |
| Symbol | ATXN7 |
| Alt. symbols | SCA7 |
| NCBI gene | 6314 |
| HGNC | 10560 |
| OMIM | 607640 |
| PDB | 7KTR |
| RefSeq | NM_000333 |
| UniProt | O15265 |
| Other data | |
| Locus | Chr. 3 p21.1-p12 |
| SUPT20H | |
|---|---|
 SUPT20H is a subunit of the SAGA coactivator complex that regulates gene expression. SPT20H holds ATXN7 down to the core of the complex. | |
| Identifiers | |
| Symbol | SUPT20H |
| Alt. symbols | SPT20H; bA421P11.4; P38IP |
| NCBI gene | 110679609 |
| HGNC | 20596 |
| PDB | 7KTR |
| RefSeq | KAI4063086.1 |
| UniProt | Q8NEM7-3 |
| Other data | |
| Locus | Chr. 3 q13.3 |
| SAGA Coactivator Complex | |
|---|---|
 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. | |
| Identifiers | |
| Symbol | SAGA or STAGA |
| Alt. symbols | Spt-Ada-Gcn5 acetyltransferase |
| PDB | 7KTR |
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.[1] The expandable poly(Q) motif region in the protein contributes crucially to spinocerebellar ataxia (SCA) pathogenesis by the induction of intranuclear inclusion bodies.[2] ATXN7 is associated with both olivopontocerebellar atrophy type 3 (OPCA3) and spinocerebellar ataxia type 7 (SCA7).
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.[3] 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.[4] Research suggest that silencing of ATXN7 in the retina by RNAi can be a possible therapeutic strategy for patients with SCA7 retinal degeneration.[5]
The N-terminus of ATXN7 is attached to a structural scaffold protein in the SAGA complex, SUPT20H.[6] 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.[6][7] 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.[6][7] Because of the length of the interaction being 3.3Å, it is characterized as a hydrogen bond keeping the two proteins attached.
References
- ↑ "Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization". eLife 8 (e49677). 26 July 2019. doi:10.7554/eLife.49677. PMID 31348003.
- ↑ "Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics". Human Molecular Genetics 12 (21): 2845–2852. November 2003. doi:10.1093/hmg/ddg297. PMID 12944423.
- ↑ "A Complete Association of an intronic SNP rs6798742 with Origin of Spinocerebellar Ataxia Type 7-CAG Expansion Loci in the Indian and Mexican Population". Ann Hum Genet 81 (5): 197–204. September 2017. doi:10.1111/ahg.12200. PMID 28597910.
- ↑ Wolfe, Michael S. (18 April 2018). The molecular and cellular basis of neurodegenerative diseases: underlying mechanisms. Elsevier Science. ISBN 978-0-12-811304-2. OCLC 1040033113.
- ↑ "RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration". PLOS ONE 9 (4). 2014. doi:10.1371/journal.pone.0095362. PMID 24759684. Bibcode: 2014PLoSO...995362R.
- ↑ 6.0 6.1 6.2 Herbst, Dominik A.; Esbin, Meagan N.; Louder, Robert K.; Dugast-Darzacq, Claire; Dailey, Gina M.; Fang, Qianglin; Darzacq, Xavier; Tjian, Robert et al. (December 2021). "Structure of the human SAGA coactivator complex" (in en). Nature Structural & Molecular Biology 28 (12): 989–996. doi:10.1038/s41594-021-00682-7. ISSN 1545-9985. PMID 34811519.
- ↑ 7.0 7.1 Zhang, Yuzhu; Yin, Changping; Yin, Yue; Wei, Mengqi; Jing, Wei; Peng, Chao; Chen, Zhengjun; Huang, Jing (2022-11-22). "Cryo-EM structure of human SAGA transcriptional coactivator complex" (in en). Cell Discovery 8 (1): 125. doi:10.1038/s41421-022-00489-w. ISSN 2056-5968. PMID 36414614.
Further reading
- "PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins". The Journal of Cell Biology 174 (1): 65–76. July 2006. doi:10.1083/jcb.200511045. PMID 16818720.
- "Both normal and polyglutamine- expanded ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase- containing complexes". Biochemical Society Symposium 73 (73): 155–163. 2006. doi:10.1042/bss0730155. PMID 16626296.
- "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. April 2006. doi:10.1016/j.cellsig.2005.05.024. PMID 15964171.
- "Ataxin-7 aggregation and ubiquitination in infantile SCA7 with 180 CAG repeats". Annals of Neurology 56 (3): 448–452. September 2004. doi:10.1002/ana.20230. PMID 15349877.
- "Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes". Human Molecular Genetics 13 (12): 1257–1265. June 2004. doi:10.1093/hmg/ddh139. PMID 15115762.
External links
- GeneReviews/NCBI/NIH/UW entry on Spinocerebellar Ataxia Type 7
- ataxin-7 at the US National Library of Medicine Medical Subject Headings (MeSH)
- Online Mendelian Inheritance in Man (OMIM) 164500
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