title: Structure-Based Identification of HDAC8 Non-histone Substrates.
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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Nawsad
authors.initials: N
authors.lastname: Alam
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Zimmerman
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Wolfson
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Caleb G
authors.initials: CG
authors.lastname: Joseph
authors.affiliation: 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.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Fierke
authors.affiliation: 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.
authors.forename: Ora
authors.initials: O
authors.lastname: Schueler-Furman
mesh_terms: D000107:Acetylation; D000465:Algorithms; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases