Hydroxamic acid-modified peptide library provides insights into the molecular basis for the substrate selectivity of HDAC corepressor complexes

Archibald, L. J., Brown, E. A., Millard, C. J., Watson, P. J., Robertson, N. S., Wang, S., Schwabe, J. W. R. and Jamieson, A. G. (2022) Hydroxamic acid-modified peptide library provides insights into the molecular basis for the substrate selectivity of HDAC corepressor complexes. ACS Chemical Biology, 17(9), pp. 2572-2582. (doi: 10.1021/acschembio.2c00510) (PMID:35973051) (PMCID:PMC9488896)

Abstract

Targeting the lysine deacetylase activity of class I histone deacetylases (HDACs) is potentially beneficial for the treatment of several diseases including human immunodeficiency virus (HIV) infection, Alzheimer’s disease, and various cancers. It is therefore important to understand the function and mechanism of action of these enzymes. Class I HDACs act as catalytic components of seven large, multiprotein corepressor complexes. Different HDAC corepressor complexes have specific, nonredundant roles in the cell. It is likely that their specific functions are at least partly influenced by the substrate specificity of the complexes. To address this, we developed chemical tools to probe the specificity of HDAC complexes. We assessed a library of acetyl-lysine-containing substrate peptides and hydroxamic acid-containing inhibitor peptides against the full range of class I HDAC corepressor complexes. The results suggest that site-specific HDAC corepressor complex activity is driven in part by the recognition of the primary amino acid sequence surrounding a particular lysine position in the histone tail.

• Item Type: Articles
• Additional Information: This work was supported by Wellcome Trust grants (100237/ Z/12/Z and 222493/Z/21/Z) to J.W.R.S. and an EPSRC Research Project Grant (EP/N034295/1) to A.G.J. L.J.A. thanks the EPSRC for a studentship (EP/M506539/1 and EP/ N509668/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Andrew and Archibald, Dr Lewis
• Authors: Archibald, L. J., Brown, E. A., Millard, C. J., Watson, P. J., Robertson, N. S., Wang, S., Schwabe, J. W. R., and Jamieson, A. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Science and Engineering > School of Chemistry
• Journal Name: ACS Chemical Biology
• Publisher: American Chemical Society
• ISSN: 1554-8929
• ISSN (Online): 1554-8937
• Published Online: 16 August 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in ACS Chemical Biology 17(9): 2572-2582
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190790		EPSRC DTG 2014	Mary Beth Kneafsey	Engineering and Physical Sciences Research Council (EPSRC)	EP/M506539/1	Research and Innovation Services
172865		EPSRC DTP 16/17 and 17/18	Mary Beth Kneafsey	Engineering and Physical Sciences Research Council (EPSRC)	EP/N509668/1	Research and Innovation Services