Structure-Based Identification of HDAC8 Non-histone Substrates

Nawsad Alam; Lior Zimmerman; Noah A Wolfson; Caleb G Joseph; Carol A Fierke; Ora Schueler-Furman

doi:10.1016/j.str.2016.02.002

Structure-Based Identification of HDAC8 Non-histone Substrates

Structure. 2016 Mar 1;24(3):458-68. doi: 10.1016/j.str.2016.02.002.

Authors

Nawsad Alam¹, Lior Zimmerman¹, Noah A Wolfson², Caleb G Joseph³, Carol A Fierke⁴, Ora Schueler-Furman⁵

Affiliations

¹ Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
² Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
³ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
⁴ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA; Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
⁵ Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel. Electronic address: oraf@ekmd.huji.ac.il.

Abstract

HDAC8 is a member of the family of histone deacetylases (HDACs) that catalyze the deacetylation of acetyl lysine residues within histone and non-histone proteins. The recent identification of novel non-histone HDAC8 substrates such as SMC3, ERRα, and ARID1A indicates a complex functionality of this enzyme in cellular homeostasis. To discover additional HDAC8 substrates, we developed a comprehensive, structure-based approach based on Rosetta FlexPepBind, a protocol that evaluates peptide-binding ability to a receptor from structural models of this interaction. Here we adapt this protocol to identify HDAC8 substrates using peptide sequences extracted from proteins with known acetylated sites. The many new in vitro HDAC8 peptide substrates identified in this study suggest that numerous cellular proteins are HDAC8 substrates, thus expanding our view of the acetylome and its regulation by HDAC8.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Algorithms
Binding Sites
Computational Biology / methods*
Computer Simulation
Histone Deacetylases / chemistry*
Histone Deacetylases / metabolism*
Humans
Models, Molecular
Peptides / chemistry*
Peptides / metabolism*
Protein Binding
Repressor Proteins / chemistry*
Repressor Proteins / metabolism*
Substrate Specificity

Substances

Peptides
Repressor Proteins
HDAC8 protein, human
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding