Year: 2023
Type: article
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.
Source: Nature Communications
Authors: Avinash B. Patel, Jinkang Qing, Kelly H. Tam, Sara Zaman, Maria Luiso, Ishwar Radhakrishnan, Yuan He
Institution: Northwestern University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, American Heart Association, Oregon Health and Science University, Northwestern University, Sherman Fairchild Foundation, National Institutes of Health, Office of Science, Robert H. Lurie Comprehensive Cancer Center, National Cancer Institute, National Institute of General Medical Sciences, Biological and Environmental Research
Awards: G1054907967, G1134986053, G1164661550, G1284175734, G157102116, Structure and Mechanism of Eukaryotic Transcription Regulation, National Resource for Translational and Developmental Proteomics, G317886719, G3319559482, Structural Cell Biology of DNA Repair Machines, G3508161151, G4020378667, G4159268500, Structure and Mechanism of Non-Homologous End Joining, G5718375046, G6221506569, G6780141363, Acquisition of a Thermo Fisher Scientific Q Exactive UHMR mass spectrometer, G727633814, Biochemical and Structural Studies of the Sin3L/HDAC Complex, G7562546725, G7673727097, G7913850483, G9000002633, G9000046704, G9000060489, G9000085949, G9000328203, G9000345326, The Robert H. Lurie Comprehensive Cancer Center
OpenAlex ID: W4378527517