Alternative splicing generates multiple SMRT transcripts encoding conserved repressor domains linked to variable transcription factor interaction domains

Silencing mediator for retinoid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor protein (NCoR) are corepressors that interact with a range of transcription factors. They both consist of N-terminal repressor domains that associate with histone deacetylases and C-terminal interaction domains (IDs) that contain CoRNR box motifs. These motifs mediate the interaction between corepressors and nuclear receptors (NRs), such as the retinoid and thyroid hormone receptors. However, whilst NCoR produces a single transcript during Xenopus development, xSMRT is subject to alternative splicing at four sites in the 3' part of the transcript, the region encoding the C-terminal IDs. Although this provides the potential to produce 16 different transcripts, only five isoforms are found in early embryos. The sites of alternative splicing predict that the resultant isoforms will differ in their ability to interact with NRs, as one site varies the number of CoRNR boxes, the second site changes the sequence flanking CoRNR box-1 and the other sites delete amino acid residues between CoRNR boxes 1 and 2 and so alter the critical spacing between these motifs. SMRT and NCoR therefore represent paralogues in which one form, SMRT, has evolved the ability to generate multiple isoforms whereas the other, NCoR, is invariant in Xenopus development.