Abstract
The Rpd3L histone deacetylase (HDAC) complex is an ancient 12-subunit complex conserved in a broad range of eukaryotes that performs localized deacetylation at or near sites of recruitment by DNA-bound factors. Here we describe the cryo-EM structure of this prototypical HDAC complex that is characterized by as many as seven subunits performing scaffolding roles for the tight integration of the only catalytic subunit, Rpd3. The principal scaffolding protein, Sin3, along with Rpd3 and the histone chaperone, Ume1, are present in two copies, with each copy organized into separate lobes of an asymmetric dimeric molecular assembly. The active site of one Rpd3 is completely occluded by a leucine side chain of Rxt2, while the tips of the two lobes and the more peripherally associated subunits exhibit varying levels of flexibility and positional disorder. The structure reveals unexpected structural homology/analogy between unrelated subunits in the fungal and mammalian complexes and provides a foundation for deeper interrogations of structure, biology, and mechanism of these complexes, as well as for the discovery of HDAC complex-specific inhibitors.
Original language | English (US) |
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Article number | 3061 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2023 |
Funding
We thank Jason Pattie for computer support, Janette Meyers at the PNCC for data collection support and Yongbo Zhang for assistance with NMR experiments. We are grateful to the National Institutes of Health and the Robert H. Lurie Comprehensive Cancer Center for supporting structural biology and proteomics research at Northwestern (P30 CA060553, S10 OD025194, and P41 GM108569). The studies described herein were supported in part by the National Institutes of Health (R01GM135651, R01GM144559, and P01CA092584 to Y.H.), the American Heart Association (17GRNT33680167 to I.R.), the H Foundation, and the Sherman Fairchild Foundation (I.R.) and the Baker Program in Undergraduate Research at Northwestern (K.H.T, S.Z., M.L., and I.R.). A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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Structure of the yeast (HDAC) Rpd3L complex
Patel, A. B. (Contributor), Qing, J. (Contributor), Tam, K. H. (Contributor), Zaman, S. (Contributor), Luiso, M. (Contributor), Radhakrishnan, I. (Contributor) & He, Y. (Contributor), Protein Data Bank (PDB), Jul 12 2023
DOI: 10.2210/pdb8GA8/pdb, https://www.wwpdb.org/pdb?id=pdb_00008ga8
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