Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors
Open accessAbstract
SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a C-terminal SANT (SWI3/ADA2/NCoR/TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that ( i ) it has an additional N-terminal helix and ( ii ) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.
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Previous mutagenesis of SMRT-DAD showed that all mutations that failed to activate HDAC3 also abolished or significantly impaired interaction, including mutations of Lys449, Tyr470 and Tyr471, which play a key role in binding Ins(1,4,5,6)P4.
“These conclusions are supported by our previous mutagenesis study of the SMRT-DAD in which we looked at the effect of mutations on both the interaction with, and the deacetylase activity of, HDAC3. All mutations that failed to activate HDAC3 also abolished, or significantly impaired, interaction. These include mutations of Lys449, Tyr470 and Tyr471 which play a key role in binding the Ins(1,4,5,6)”
From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [31]
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Experimental — accuracy not yet measuredThe previously reported structure of the isolated DAD from SMRT revealed that part of the DAD-specific motif forms an extra helix folded against the three helices of the SANT domain to form a four-helix bundle, and the amino-terminal portion of the DAD-specific motif is unstructured in solution.
“We have previously reported the structure of the isolated DAD from SMRT31. This revealed that part of the DAD-specific motif forms an extra helix that is folded against the three helices of the SANT domain to form a four-helix bundle. The amino-terminal portion of the DAD-specific motif is unstructured in solution31.”
From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [31]
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- Authors
- Codina, A., Love, J. D., Li, Y., Lazar, M. A., Neuhaus, D., & Schwabe, J. W. R.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Schwabe, John W. R.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-04-18
- Volume
- 102
- Issue
- 17
- Pages
- 6009-6014
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1087922
- OpenAlex
- W2160093177
- Cited by
- 95
- References
- 40
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 6 · 2012: 3
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- European Commission
- National Institutes of Health (DK43806)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK43806, R01DK045586, DK 45586, R37DK043806, R01DK043806)
- 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 › Molecular Biology › Protein Structure and Dynamics
- Keywords
- HDAC3, SMRT, NCoR, nuclear receptor corepressor, SANT domain, solution structure, protein-protein interaction, hydrophobic groove, lysine residues, transcriptional repression, corepressors
- MeSH terms
- Histone Deacetylase 3, Amino Acid Sequence, Calorimetry, Enzyme Activation, Escherichia coli, Histone Deacetylases, Kinetics, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Protein Conformation, Recombinant Proteins, Repressor Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Protein Structure, Secondary, Nuclear Receptor Co-Repressor 1
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