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Notch signaling plays a fundamental role in the regulation of diverse biological processes. In the absence of Notch signaling, DNA-bound CSL [CBF1/Su(H)/Lag-1] factor represses gene expression via the direct recruitment of corepressor proteins, including silencing mediator of retinoid and thyroid receptor (SMRT) and KyoT2. Structural studies have unveiled the molecular basis of these interactions in which corepressors bind to CSL using a conserved ΦWΦP motif (Φ: any hydrophobic residues). Here, we comparatively analyzed the CSL-binding motifs of SMRT (1830EHAPIWRP1837) and KyoT2 (186VKAPVWWP193) using swap mutants. Various in vivo and in vitro binding assays confirmed that V186 and W192 residues of KyoT2 are major determinants for high affinity binding to CSL. We designed a peptide with the chimeric sequence (VHAPIWWP) of CSL-binding motifs of SMRT and KyoT2. Intriguingly, this peptide acts as an in vivo competitor of endogenous corepressor proteins and an artificial activator for the transcriptional activity of NICD.
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참고문헌 (30)
참고문헌 신청
Ann, E. J. / 2012 / Wnt5a controls Notch1 signaling through CaMKIImediated degradation of the SMRT corepressor protein / J Biol Chem 287:36814~36829
Borggrefe, T. / 2009 / The Notch signaling pathway : transcriptional regulation at Notch target genes / Cell Mol Life Sci 66:1631~1646
Chen, J. D. / 1995 / A transcriptional co-repressor that interacts with nuclear hormone receptors / Nature 377:454~457
Choi, J. M. / 2006 / Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation / Nat Med 12:574~579
Collins, K. J. / 2014 / Structure and function of the CSL-KyoT2 corepressor complex : a negative regulator of Notch signaling / Structure 22:70~81
Borggrefe, T. / 2009 / The Notch signaling pathway : transcriptional regulation at Notch target genes / Cell Mol Life Sci 66:1631~1646
Chen, J. D. / 1995 / A transcriptional co-repressor that interacts with nuclear hormone receptors / Nature 377:454~457
Choi, J. M. / 2006 / Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation / Nat Med 12:574~579
Collins, K. J. / 2014 / Structure and function of the CSL-KyoT2 corepressor complex : a negative regulator of Notch signaling / Structure 22:70~81
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