A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling.

By M. Ariyoshi, J. Schwabe. 2003

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Spen proteins regulate the expression of key transcriptional effectors in diverse signaling pathways. They are large proteins characterized by N-terminal RNA-binding motifs and a highly conserved C-terminal SPOC domain. The specific biological role of the SPOC domain (Spen paralog and ortholog C-terminal domain), and hence, the common function of Spen proteins, has been unclear to date. The Spen protein, SHARP (SMRT/HDAC1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and Notch/RBP-Jkappa signaling pathways. We have determined the 1.8 A crystal structure of the SPOC domain from SHARP. This structure shows that essentially all of the conserved surface residues map to a positively charged patch. Structure-based mutational analysis indicates that this conserved region is responsible for the interaction between SHARP and the universal transcriptional corepressor SMRT/NCoR (silencing mediator for retinoid and thyroid receptors/nuclear receptor corepressor. We demonstrate that this interaction involves a highly conserved acidic motif at the C terminus of SMRT/NCoR. These findings suggest that the conserved function of the SPOC domain is to mediate interaction with SMRT/NCoR corepressors, and that Spen proteins play an essential role in the repression complex.

Subfields: Molecular Biology

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Citations in the corpus

Structural insights into the recruitment of SMRT by the corepressor SHARP under phosphorylative regulation. (2013, background): “Ariyoshi and Schwabe (2003) previously described the interaction surface as deduced from the inspection of crystal packing and mutagenesis.”
A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive chromatin state at Notch target genes (2016, background): “Based on the previous crystal structure of the SPOC domain (42) (Figure 3A), we generated a double mutant [SPOC(R3552A/R3554A)] that no longer interacts with NCoR (Figure 3B).”
Crystal Structure of the SPOC Domain of the Arabidopsis Flowering Regulator FPA (2016, methodology): “The top hit is the SPOC domain of human SHARP [15,16] (Fig 3A), with a Z score of 12.”
Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing (2015, background): “…regulation of Notch pathway and 82 steroid receptor-dependent transcriptional regulation, and to recruit MLL complexes to promoters for 83 histone H3K4 methylation (Ariyoshi and Schwabe, 2003; Lee and Skalnik, 2012; Ma et al., 2007; Oswald 84 et al., 2002; Shi et al., 2001; Xiao et al., 2015).”
RBP-Jκ/SHARP Recruits CtIP/CtBP Corepressors To Silence Notch Target Genes (2005, background): “Previous studies have shown that the evolutionarily conserved repression domain of SHARP (SHARP-RD), also called the SPOC (Spen paralog and ortholog C-terminal) domain, resides at the C terminus (1, 20, 27).”
Structures of RNA polymerase II complexes with Bye1, a chromatin-binding PHF3/DIDO homologue (2013, background): “The function of SPOC domains in yeast is unclear, but in higher eukaryotes, SPOC domains are implicated in developmental signaling (18).”
Time-resolved structured illumination microscopy reveals key principles of Xist RNA spreading (2020, background): “To discriminate these possibilities, we generated mESCs with mutations in the SPOC domain (SPEN), previously shown to disrupt interaction with the NCoR/HDAC3 co-repressor (29) (Fig.”