title: Inactivating mutation in histone deacetylase 3 stabilizes its active conformation.
abstract: Histone deacetylases (HDACs), together with histone acetyltransferases (HATs), regulate gene expression by modulating the acetylation level of chromatin. HDAC3 is implicated in many important cellular processes, particularly in cancer cell proliferation and metastasis, making inhibition of HDAC3 a promising epigenetic treatment for certain cancers. HDAC3 is activated upon complex formation with both inositol tetraphosphate (IP4) and the deacetylase-activating domain (DAD) of multi-protein nuclear receptor corepressor complexes. In previous studies, we have shown that binding of DAD and IP4 to HDAC3 significantly restricts its conformational space towards its stable ternary complex conformation, and suggest this to be the active conformation. Here, we report a single mutation of HDAC3 that is capable of mimicking the stabilizing effects of DAD and IP4, without the presence of either. This mutation, however, results in a total loss of deacetylase activity, prompting a closer evaluation of our understanding of the activation of HDAC3.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, 92093-0365.
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Arrar
authors.forename: Cesar Augusto F
authors.initials: CA
authors.lastname: de Oliveira
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D019943:Amino Acid Substitution; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D004795:Enzyme Stability / Q000235:genetics; D006655:Histone Deacetylases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D020125:Mutation, Missense; D011392:Proline / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D000099186:Histone Deacetylase 3
chemical_list: D001120:Arginine; D006655:Histone Deacetylases; D007295:Inositol Phosphates; D011392:Proline; D000099186:Histone Deacetylase 3
keywords: HDAC3; R265P; allostery; conformational selection; molecular recognition
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