Ataxin 7

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Ataxin-7
Ataxin-7.jpg
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 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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Structures Swiss-model
Domains InterPro
SUPT20H
SPT20H.jpg
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 gene 110679609
HGNC 20596
PDB 7KTR
RefSeq KAI4063086.1
UniProt Q8NEM7-3
Other data
Locus Chr. 3 q13.3
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Structures Swiss-model
Domains InterPro
SAGA Coactivator Complex
ATXN7 and SPT20H.png
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
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).

Contents

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. ATXN7 and SPT20H Interaction.png
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

  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. 1 2 3 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. 1 2 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.

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