Cited by 32Histone Deacetylase Inhibitors ResearchGenomics and Chromatin DynamicsEnzyme Structure and Function

Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex

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Wan, Mandy S. M., Muhammad, Reyhan, Koliopoulos, Marios G., Roumeliotis, Theodoros I., Choudhary, Jyoti S., Alfieri, Claudio·2023·Nature Communications

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Abstract

Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.

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Authors
Wan, M. S. M., Muhammad, R., Koliopoulos, M. G., Roumeliotis, T. I., Choudhary, J. S., & Alfieri, C.
Affiliations
Institute of Cancer Research (GB)
Corresponding author
Alfieri, Claudio
Venue
Nature Communications
Published
2023-05-03
Volume
14
Issue
1
Pages
2556-2556
ISSN
2041-1723 (ISSN-L)
OpenAlex
W4367839625
Cited by
32
References
76
Citations by year
2026: 12 · 2025: 8 · 2024: 7 · 2023: 5
FWCI
2.84
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (215458/Z/19/Z)
  • Institute of Cancer Research, Royal Cancer Hospital (GFR146X)
  • Cancer Research UK (C309/A25144)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
SIN3B, histone deacetylase, histone deacetylase complex, histone lysine acetylation, substrate specificity, allosteric activation, substrate receptor, transcriptional repression, protein complex structure, histone modifications
MeSH terms
Acetylation, Histone Deacetylases, Histones, Humans, Lysine, Protein Processing, Post-Translational, Repressor Proteins, Saccharomyces cerevisiae, Histone Deacetylase 1

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