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

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Structure-Based Identification of HDAC8 Non-histone Substrates

Journal article

Open access

Peer reviewed

Structure-Based Identification of HDAC8 Non-histone Substrates

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

Structure (London), Vol.24(3), pp.458-468

03/01/2016

DOI: https://doi.org/10.1016/j.str.2016.02.002

PMCID: PMC5590822

PMID: 26933971

Abstract

Acetylation

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

Algorithms

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.

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Title: Structure-Based Identification of HDAC8 Non-histone Substrates
Creators: Nawsad Alam - Hebrew University of Jerusalem
Lior Zimmerman - Hebrew University of Jerusalem
Noah A Wolfson - University of Michigan–Ann Arbor
Caleb G Joseph - University of Michigan–Ann Arbor
Carol A Fierke - University of Michigan–Ann Arbor
Ora Schueler-Furman - Hebrew University of Jerusalem
Publication Details: Structure (London), Vol.24(3), pp.458-468
Grant note: GM40602 / NIGMS NIH HHS R01 GM040602 / NIGMS NIH HHS
Identifiers: 9924052787101921
Academic Unit: Department of Biochemistry
Language: English
Resource Type: Journal article

Structure-Based Identification of HDAC8 Non-histone Substrates

Abstract

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