SMRTε, a corepressor variant, interacts with a restricted subset of nuclear receptors, including the retinoic acid receptors α and β

► SMRTε is an alternatively-spliced form of corepressor. ► SMRTε expression differs in different cell types. ► SMRTε displays a restricted specificity for a subset of nuclear receptor partners. ► SMRTε interacts with nuclear receptors by a mix of α-helical and β-strand surfaces. ► SMRTε is highly specific for RARs when bound to their cognate DNA response elements. The SMRT and NCoR corepressors bind to, and mediate transcriptional repression by, many nuclear receptors. Both SMRT and NCoR are expressed by alternative mRNA splicing, generating a series of structurally and functionally distinct corepressor “variants”. We report that a splice variant of SMRT, SMRTε, recognizes a restricted subset of nuclear receptors. Unlike the other corepressor variants characterized, SMRTε possesses only a single receptor interaction domain (RID) and exhibits an unusual specificity for a subset of nuclear receptors that includes the retinoic acid receptors (RARs). The ability of the single RID in SMRTε to efficiently interact with RARs appears to be enhanced by a recently recognized β-strand/β-strand interaction between corepressor and receptor. We suggest that alternative mRNA splicing of corepressors can restrict their function to specific nuclear receptor partnerships, and we propose that this may serve to customize the transcriptional repression properties of different cell types for different biological purposes.