8a8q
From Proteopedia
Crystal structure of Protein Scalloped in complex with YAP peptide
Structural highlights
FunctionSCAL_DROME Transcription factor which plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein Hippo (Hpo), in complex with its regulatory protein Salvador (Sav), phosphorylates and activates Warts (Wts) in complex with its regulatory protein Mats, which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein. The Hippo/SWH signaling pathway inhibits the activity of the transcriptional complex formed by Scalloped (sd) and Yki and the target genes of this pathway include cyclin-E (cycE), diap1 and bantam. Sd promotes nuclear localization of Yki. Involved in the regulation of cell-specific gene expression during development, particularly in the differentiation of the nervous system. When in combination with vestigial (vg) it acts as a transcriptional activation complex that regulates gene expression in the wing. Binding to vg switches the DNA target selectivity of sd. Required autonomously for cell proliferation and viability within the wing blade. Required for proper sensory organ precursor (SOP) differentiation at the wing margin; required for correct expression of sens.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe yes-associated protein (YAP) regulates the transcriptional activity of the TEAD transcription factors that are key in the control of organ morphogenesis. YAP interacts with TEAD via three secondary structure elements: a beta-strand, an alpha-helix, and an Omega-loop. Earlier results have shown that the beta-strand has only a marginal contribution in the YAP:TEAD interaction, but we show here that it significantly enhances the affinity of YAP for the Drosophila homolog of TEAD, scalloped (Sd). Nuclear magnetic resonance shows that the beta-strand adopts a more rigid conformation once bound to Sd; pre-steady state kinetic measurements show that the YAP:Sd complex is more stable. Although the crystal structures of the YAP:TEAD and YAP:Sd complexes reveal no differences at the binding interface that could explain these results, Molecular Dynamics simulations are in line with our experimental findings regarding beta-strand stability and overall binding affinity of YAP to TEAD and Sd. In particular, RMSF, correlated motion and MMGBSA analyses suggest that beta-sheet fluctuations play a relevant role in YAP(53-57) beta-strand dissociation from TEAD4 and contribute to the lower affinity of YAP for TEAD4. Identifying a clear mechanism leading to the difference in YAP's beta-strand stability proved to be challenging, pointing to the potential relevance of multiple modest structural changes or fluctuations for regulation of binding affinity. N-terminal beta-strand in YAP is critical for stronger binding to Scalloped relative to TEAD transcription factor.,Bokhovchuk F, Mesrouze Y, Meyerhofer M, Fontana P, Zimmermann C, Villard F, Erdmann D, Kallen J, Scheufler C, Velez-Vega C, Chene P Protein Sci. 2022 Dec 15:e4545. doi: 10.1002/pro.4545. PMID:36522189[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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