Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates
Open accessAbstract
Class I histone deacetylases (HDAC1, HDAC2, and HDAC3) are recruited by cognate corepressor proteins into specific transcriptional repression complexes that target HDAC activity to chromatin resulting in chromatin condensation and transcriptional silencing. We previously reported the structure of HDAC3 in complex with the SMRT corepressor. This structure revealed the presence of inositol-tetraphosphate [Ins(1,4,5,6)P4] at the interface of the two proteins. It was previously unclear whether the role of Ins(1,4,5,6)P4 is to act as a structural cofactor or a regulator of HDAC3 activity. Here we report the structure of HDAC1 in complex with MTA1 from the NuRD complex. The ELM2-SANT domains from MTA1 wrap completely around HDAC1 occupying both sides of the active site such that the adjacent BAH domain is ideally positioned to recruit nucleosomes to the active site of the enzyme. Functional assays of both the HDAC1 and HDAC3 complexes reveal that Ins(1,4,5,6)P4 is a bona fide conserved regulator of class I HDAC complexes.
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None of these studies described comprehensive protein structures for both binding partners, so the complete interaction interfaces remain unknown.
“None of these studies described comprehensive protein structures for both binding partners, so the complete interaction interfaces remain unknown.”
From Towards elucidating the stability, dynamics and architecture of the nucleosome remodeling and deacetylase complex by using quantitative interaction proteomics (2015) · cites this paper as [29]
The Results section, “Structure of the HDAC1:MTA1 Complex” (page unavailable), says the structure used only MTA1 residues 162–335, supporting the point that it did not resolve both full-length partners. But it also describes extensive HDAC1–MTA1 contacts and measures their binding interface, so the claim that the interaction interface remains unknown overstates what this paper shows. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn hHDAC1 and hHDAC3, the corresponding arginine is involved in inositol phosphate binding and is important for activity.
“In hHDAC1 and hHDAC3 this arginine is involved in inositol phosphate binding and is important for activity 38, 47, 48 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [47]
The Results section, “The Role of Inositol Phosphate in HDAC1 and HDAC3 Corepressor Complexes” (page unavailable), reports that mutations expected to impair inositol-phosphate binding in either HDAC reduced or abolished phosphate-dependent enhancement of activity. The passages do not identify those mutations as changes to the corresponding arginine, so they do not establish the residue-specific part of the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredFew NuRD subcomplexes have resolved structures, most notably the MBD2-GATAD2A coiled-coil subcomplex, the RBBP4-MTA1 subcomplex, and the HDAC1-MTA1 subcomplex.
“Few NuRD subcomplexes have resolved structures, most notably the MBD2 -GATAD2A coiled-coil subcomplex, the RBBP4 -MTA1 subcomplex, and the HDAC1 -MTA1 subcomplex [20,29,30].”
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“The Role of Inositol Phosphate in HDAC1 and HDAC3 Corepressor Complexes Wepreviously demonstrated that Ins(1,4,5,6)P4, which copurified with the complex from mammalian cells, was essential for the interaction between HDAC3 and the extended SANT domain from the SMRT corepressor (Watson et al., 2012).”
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“Later studies suggested that higher-order inositol phosphates (such as InsP6) might also interact with HDAC1 [77].”
- Authors
- Millard, C. J., Watson, P. J., Celardo, I., Gordiyenko, Y., Cowley, S. M., Robinson, C. V., Fairall, L., & Schwabe, J. W. R.
- Affiliations
- University of Leicester (GB)
- University of Oxford (GB)
- Corresponding author
- Fairall, Louise
- Schwabe, John W.R.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 51
- Issue
- 1
- Pages
- 57-67
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3710971
- OpenAlex
- W2094383719
- Cited by
- 396
- References
- 6
- Citations by year
- 2026: 22 · 2025: 35 · 2024: 26 · 2023: 25 · 2022: 26 · 2021: 30 · 2020: 29 · 2019: 43 · 2018: 26 · 2017: 29 · 2016: 26 · 2015: 48 · 2014: 22 · 2013: 9
- FWCI
- 15.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (100237, 085408)
- Medical Research Council (MR/J009202/1)
- Biotechnology and Biological Sciences Research Council (BB/J009598/1)
- 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 › Epigenetics and DNA Methylation
- Keywords
- class I histone deacetylases, HDAC1, HDAC3, inositol tetrakisphosphate, inositol phosphates, MTA1, NuRD complex, SMRT corepressor, BAH domain, transcriptional repression, chromatin condensation, transcriptional silencing, protein complex structure
- MeSH terms
- Amino Acid Sequence, Histone Deacetylases, Humans, Inositol Phosphates, Models, Molecular, Molecular Sequence Data, Repressor Proteins, Substrate Specificity, Trans-Activators, Protein Structure, Tertiary, Protein Folding, Dimerization, Histone Deacetylase 1, HEK293 Cells
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