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KMID : 0578320180410090842
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Molecules and Cells
2018 Volume.41 No. 9 p.842 ~ p.852
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OPTHiS Identifies the Molecular Basis of the Direct Interaction between CSL and SMRT Corepressor
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Kim Gwang-Sik
Park Hee-Sae
Lee Young-Chul
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Abstract
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Notch signaling is an evolutionarily conserved pathway and involves in the regulation of various cellular and developmental processes. Ligand binding releases the intracellular domain of Notch receptor (NICD), which interacts with DNA-bound CSL [CBF1/Su(H)/Lag-1] to activate transcription of target genes. In the absence of NICD binding, CSL down-regulates target gene expression through the recruitment of various corepressor proteins including SMRT/NCoR (silencing mediator of retinoid and thyroid receptors/nuclear receptor corepressor), SHARP (SMRT/HDAC1-associated repressor protein), and KyoT2. Structural and functional studies revealed the molecular basis of these interactions, in which NICD coactivator and corepressor proteins competitively bind to β-trefoil domain (BTD) of CSL using a conserved ?W?P motif (? denotes any hydrophobic residues). To date, there are conflicting ideas regarding the molecular mechanism of SMRTmediated repression of CSL as to whether CSL-SMRT interaction is direct or indirect (via the bridge factor SHARP). To solve this issue, we mapped the CSL-binding region of SMRT and employed a ‘one- plus two-hybrid system’ to obtain CSL interaction- defective mutants for this region. We identified the CSL-interaction module of SMRT (CIMS; amino acid 1816- 1846) as the molecular determinant of its direct interaction with CSL. Notably, CIMS contains a canonical ?W?P sequence (APIWRP, amino acids 1832?1837) and directly interacts with CSL-BTD in a mode similar to other BTD-binding corepressors. Finally, we showed that CSL-interaction motif, rather than SHARP-interaction motif, of SMRT is involved in transcriptional repression of NICD in a cell-based assay. These results strongly suggest that SMRT participates in CSL-mediated repression via direct binding to CSL.
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KEYWORD
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CSL, Notch, OPTHiS, SMRT, ?W?P motif
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