Structural Insights into the Recruitment of SMRT by the Corepressor SHARP under Phosphorylative Regulation

The transcriptional corepressors SMRT/NCoR, components of histone deacetylase complexes, interact with nuclear receptors and many other transcription factors. SMRT is a target for the ubiquitously expressed protein kinase CK2, which is known to phosphorylate a wide variety of substrates. Increasing evidence suggests that CK2 plays a regulatory role in many cellular events, particularly, in transcription. However, little is known about the precise mode of action involved. Here, we report the three-dimensional structure of a SMRT/HDAC1-associated repressor protein (SHARP) in complex with phosphorylated SMRT, as determined by solution NMR. Phosphorylation of the CK2 site on SMRT significantly increased affinity for SHARP. We also confirmed the significance of CK2 phosphorylation by reporter assay and propose a mechanism involving the process of phosphorylation acting as a molecular switch. Finally, we propose that the SPOC domain functions as a phosphorylation binding module. [Display omitted] •Phosphorylation of SMRT by CK2 significantly enhances the affinity to SPOC domain•Structure of the SPOC domain in complex with phosphorylated SMRT has been determined•We propose that the SPOC domain is a phosphodependent protein-interaction domain The transcriptional corepressor SMRT is a target for CK2. Mikami et al. report a structure of the SPOC domain of SMRT/HDAC1-associated repressor protein (SHARP) in complex with the phosphorylated SMRT peptide. This suggests that the SPOC domain is a new phosphorylation binding module.