Characterization of molecular interactions between HDAC7 and MEF2A.

Abstract

Interactions of transcriptional corepressors such as histone deacetylase 7 (HDAC7), a class IIa HDAC, with myocyte enhancer factor-2 (MEF2) regulate MEF2 activity. Despite previous investigations exploring interactions between HDAC7 and MEF2, a detailed characterization of the HDAC7-MEF2 functional complex is still lacking. Herein, we first modeled the structure of the HDAC7-MEF2A complex and investigated the inter-protein interactions using all-atom molecular dynamics (MD) simulations. We identified specific amino acids within HDAC7 and MEF2A that participate in interactions such as salt bridges, hydrogen bonds, and hydrophobic interactions. Our results reveal a salt bridge formed between LYS96(HDAC7) and ASP63(MEF2A). Our analysis also predicted formations of reliable hydrogen bonds between SER82(HDAC7) and ASP63(MEF2A) as well as LYS96(HDAC7) and ASP63(MEF2A). In addition, clustering of hydrophobic residues at the interface contributes in stabilizing the HDAC7-MEF2A complex. Results from multiple sequence alignment show that most of the HDAC7 residues that are predicted to associate with MEF2A are conserved in at least three class IIa HDACs and all predicted residues in MEF2A are conserved in MEF2s. We also found that the association of DNA to MEF2A has no significant effect on HDAC7-MEF2A interactions. Our results may also provide useful insights into the interactions between other class IIa HDACs and MEF2s.