Dishevelled2 activates WGEF via its interaction with a unique internal peptide motif of the GEF

Commun Biol. 2024 May 7;7(1):543. doi: 10.1038/s42003-024-06194-6.

Abstract

The Wnt-planar cell polarity (Wnt-PCP) pathway is crucial in establishing cell polarity during development and tissue homoeostasis. This pathway is found to be dysregulated in many pathological conditions, including cancer and autoimmune disorders. The central event in Wnt-PCP pathway is the activation of Weak-similarity guanine nucleotide exchange factor (WGEF) by the adapter protein Dishevelled (Dvl). The PDZ domain of Dishevelled2 (Dvl2PDZ) binds and activates WGEF by releasing it from its autoinhibitory state. However, the actual Dvl2PDZ binding site of WGEF and the consequent activation mechanism of the GEF have remained elusive. Using biochemical and molecular dynamics studies, we show that a unique "internal-PDZ binding motif" (IPM) of WGEF mediates the WGEF-Dvl2PDZ interaction to activate the GEF. The residues at P2, P0, P-2 and P-3 positions of IPM play an important role in stabilizing the WGEFpep-Dvl2PDZ interaction. Furthermore, MD simulations of modelled Dvl2PDZ-WGEFIPM peptide complexes suggest that WGEF-Dvl2PDZ interaction may differ from the reported Dvl2PDZ-IPM interactions. Additionally, the apo structure of human Dvl2PDZ shows conformational dynamics different from its IPM peptide bound state, suggesting an induced fit mechanism for the Dvl2PDZ-peptide interaction. The current study provides a model for Dvl2 induced activation of WGEF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Dishevelled Proteins* / chemistry
  • Dishevelled Proteins* / genetics
  • Dishevelled Proteins* / metabolism
  • Guanine Nucleotide Exchange Factors* / chemistry
  • Guanine Nucleotide Exchange Factors* / genetics
  • Guanine Nucleotide Exchange Factors* / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • Molecular Dynamics Simulation*
  • PDZ Domains
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding*
  • Wnt Signaling Pathway

Substances

  • Dishevelled Proteins
  • Guanine Nucleotide Exchange Factors
  • DVL2 protein, human
  • Peptides
  • CCDC88C protein, human
  • Microfilament Proteins
  • Intracellular Signaling Peptides and Proteins