Ataxin 7
Ataxin-7 | |||||||
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![]() 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 | ||||||
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SUPT20H | |||||||
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![]() 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 | ||||||
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SAGA Coactivator Complex | |
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![]() 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.
![](http://upload.wikimedia.org/wikipedia/commons/thumb/c/c5/ATXN7_and_SPT20H_Interaction.png/307px-ATXN7_and_SPT20H_Interaction.png)
References
[edit]- ^ Cloud V, Thapa A, Morales-Sosa P, Miller TM, Miller SA, Holsapple D, et al. (26 July 2019). "Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization". Elife. 8 (e49677). doi:10.7554/eLife.49677. PMC 6693919. PMID 31348003.
- ^ Scheel H, Tomiuk S, Hofmann K (November 2003). "Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics". Human Molecular Genetics. 12 (21): 2845–2852. doi:10.1093/hmg/ddg297. PMID 12944423.
- ^ Faruq M, Magaña JJ, Suroliya V, Narang A, Murillo-Melo NM, Hernández-Hernández O, et al. (September 2017). "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. doi:10.1111/ahg.12200. PMID 28597910.
- ^ Wolfe MS (18 April 2018). Wolfe MS (ed.). The molecular and cellular basis of neurodegenerative diseases: underlying mechanisms. Elsevier Science. ISBN 978-0-12-811304-2. OCLC 1040033113.
- ^ Ramachandran PS, Bhattarai S, Singh P, Boudreau RL, Thompson S, Laspada AR, et al. (2014). "RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration". PLOS ONE. 9 (4): e95362. Bibcode:2014PLoSO...995362R. doi:10.1371/journal.pone.0095362. PMC 3997397. PMID 24759684.
- ^ a b c Herbst DA, Esbin MN, Louder RK, Dugast-Darzacq C, Dailey GM, Fang Q, et al. (December 2021). "Structure of the human SAGA coactivator complex". Nature Structural & Molecular Biology. 28 (12): 989–996. doi:10.1038/s41594-021-00682-7. ISSN 1545-9985. PMC 8660637.
- ^ a b Zhang Y, Yin C, Yin Y, Wei M, Jing W, Peng C, et al. (2022-11-22). "Cryo-EM structure of human SAGA transcriptional coactivator complex". Cell Discovery. 8 (1): 1–4. doi:10.1038/s41421-022-00489-w. ISSN 2056-5968. PMC 9681738.
Further reading
[edit]- Janer A, Martin E, Muriel MP, Latouche M, Fujigasaki H, Ruberg M, et al. (July 2006). "PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins". The Journal of Cell Biology. 174 (1): 65–76. doi:10.1083/jcb.200511045. PMC 2064165. PMID 16818720.
- 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. PMID 16626296.
- Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY, et al. (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. PMID 15964171.
- Ansorge O, Giunti P, Michalik A, Van Broeckhoven C, Harding B, Wood N, et al. (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. PMID 15349877. S2CID 8148133.
- Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C, et al. (June 2004). "Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes". Human Molecular Genetics. 13 (12): 1257–1265. doi:10.1093/hmg/ddh139. PMID 15115762.
External links
[edit]- GeneReviews/NCBI/NIH/UW entry on Spinocerebellar Ataxia Type 7
- ataxin-7 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Online Mendelian Inheritance in Man (OMIM): 164500