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Protein Sci. 2013 Oct;22(10):1306-12. doi: 10.1002/pro.2317. Epub 2013 Aug 19.

Inactivating mutation in histone deacetylase 3 stabilizes its active conformation.

Author information

1
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, 92093-0365.

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.

KEYWORDS:

HDAC3; R265P; allostery; conformational selection; molecular recognition

PMID:
23904210
PMCID:
PMC3795489
DOI:
10.1002/pro.2317
[Indexed for MEDLINE]
Free PMC Article
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