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

The silencing mediator of retinoid and thyroid hormone receptors (SMRT) has been shown to play an important role in adipogenesis and PPARgamma transcriptional activity. SMRT contains two interacting domains that mediate interactions with nuclear receptors. Interestingly, SMRT is recruited to PPARgamma via its C-terminal interacting domain, and mutation of the proximal interacting domain does not interfere with recruitment via PPARgamma. To understand how the distal interacting domain mediates recruitment by PPARgamma, 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 PPARgamma, but not for a related receptor, RARalpha. Furthermore, naturally occurring SMRT isoforms that differ in interacting domain sequences have different effects on PPARgamma as opposed to RARalpha recruitment. These data suggest that PPARgamma and RARalpha 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.