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N-terminal β-strand in YAP is critical for stronger binding to Scalloped relative to TEAD transcription factor.

Fedir BokhovchukYannick MesrouzeMarco MeyerhoferPatrizia FontanaCatherine ZimmermannFrédéric VillardDirk ErdmannJoerg KallenClemens ScheuflerCamilo Velez-VegaPatrick Chène
Published in: Protein science : a publication of the Protein Society (2022)
The 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 β-strand, an α-helix, and an Ω-loop. Earlier results have shown that the β-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 β-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 β-strand stability and overall binding affinity of YAP to TEAD and Sd. In particular, RMSF, correlated motion and MMGBSA analyses suggest that β-sheet fluctuations play a relevant role in YAP 53-57 β-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 β-strand stability proved to be challenging, pointing to the potential relevance of multiple modest structural changes or fluctuations for regulation of binding affinity.
Keyphrases
  • transcription factor
  • molecular dynamics simulations
  • magnetic resonance
  • dna binding
  • magnetic resonance imaging
  • gene expression
  • binding protein
  • single cell
  • climate change
  • molecular docking
  • contrast enhanced