SMRT recruitment by PPARγ is mediated by specific residues located in its carboxy-terminal interacting domain

Abstract

The silencing mediator of retinoid and thyroid hormone receptors (SMRT) has been shown to play an important role in adipogenesis and PPARγ transcriptional activity. SMRT contains two interacting domains that mediate interactions with nuclear receptors. Interestingly, SMRT is recruited to PPARγ via its C-terminal interacting domain, and mutation of the proximal interacting domain does not interfere with recruitment via PPARγ. To understand how the distal interacting domain mediates recruitment by PPARγ, we have now mutated residues in this domain to the corresponding amino acids found in the proximal domain. We show that specific residues in this distal domain are vital for interactions with PPARγ, but not for a related receptor, RARα. Furthermore, naturally occurring SMRT isoforms that differ in interacting domain sequences have different effects on PPARγ as opposed to RARα recruitment. These data suggest that PPARγ and RARα interact with SMRT via distinct mechanisms. These differences will be important as ligands are designed that lead to specific patterns of nuclear receptor recruitment of corepressors.