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Ataxin 7

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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
SymbolATXN7
Alt. symbolsSCA7
NCBI gene6314
HGNC10560
OMIM607640
PDB7KTR
RefSeqNM_000333
UniProtO15265
Other data
LocusChr. 3 p21.1-p12
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StructuresSwiss-model
DomainsInterPro
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
SymbolSUPT20H
Alt. symbolsSPT20H; bA421P11.4; P38IP
NCBI gene110679609
HGNC20596
PDB7KTR
RefSeqKAI4063086.1
UniProtQ8NEM7-3
Other data
LocusChr. 3 q13.3
Search for
StructuresSwiss-model
DomainsInterPro
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
SymbolSAGA or STAGA
Alt. symbolsSpt-Ada-Gcn5 acetyltransferase
PDB7KTR

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.

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.

References

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  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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

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