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
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.

References

  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. PMID 34811519.
  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): 125. doi:10.1038/s41421-022-00489-w. ISSN 2056-5968. PMC 9681738. PMID 36414614.

Further reading

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