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)

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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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190790EPSRC DTG 2014Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/M506539/1Research and Innovation Services
172865EPSRC DTP 16/17 and 17/18Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/N509668/1Research and Innovation Services