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Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex
Open accessPreprint — published as 10.1038/s41467-023-38276-0 · Paper page
Abstract
Histone deacetylase complexes remove histone lysine acetylation, a key post-translational modification that activates transcription at 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 first 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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Highly accurate protein structure prediction with AlphaFold
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Metadata
- 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
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2023-01-26
- Volume
- 14
- Issue
- 1
- Pages
- 2556-2556
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10156912
- OpenAlex
- W4367839625
- Cited by
- 32
- References
- 1
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 7 · 2023: 5
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- 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)
- Cancer Research UK (C309/A25144)
- Institute of Cancer Research (GFR146X)
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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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