Biochemical and Structural Bases of Histone Deacetylase Assembly in Corepressor Complexes

Histone deacetylases (HDACs) have emerged as targets for treating a variety of pathological conditions including cancers, inflammatory disorders, cardiovascular, neurodegenerative, and infectious diseases. Nuclear HDACs – and HDAC2 in particular – have been implicated in promoting cardiac hypertrophy, thus making them attractive targets for selective inhibition. However, little is known at the molecular level regarding how these HDACs are incorporated into giant multi-protein corepressor complexes through protein-protein interactions. This proposal seeks to fill this critical gap in our knowledge by characterizing the interactions involving the paralogous HDAC1 and HDAC2 enzymes with the three core subunits unique to the 1.2-2 MDa Sin3L corepressor complex including Sin3A, SAP30 and Sds3 that have also been implicated in important roles in cardiac biology. Our goals in this proposal are (i) to determine the structure of the complex formed by a novel zinc finger motif of SAP30 and HDAC2 and evaluate the role of inositol-3,4,5,6-tetraphosphate both structurally and functionally in regulating the interaction as well as in modulating catalytic activity and (ii) to clarify the precise molecular roles of Sin3A, SAP30, and Sds3 in recruiting HDAC1/2 to the complex and in modulating catalytic activity using biochemical and biophysical approaches. These studies will provide a mechanistic understanding of HDAC regulation and corepressor complex assembly and pave the way for higher-resolution structural studies, both of which have implications in the design and development of isozyme-selective HDAC inhibitors for treating cardiovascular diseases.