8YR7

Crystal structure of human dishevelled 2 (Dvl2) PDZ domain fused with WGEF internal peptide motif

8YR7 の概要

• エントリーDOI: 10.2210/pdb8yr7/pdb
• 分子名称: Segment polarity protein dishevelled homolog DVL-2,Rho guanine nucleotide exchange factor 19 (1 entity in total)
• 機能のキーワード: wnt signaling, signaling protein
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11607.19

構造登録者

Omble, A.,Mahajan, S.,Kulkarni, K.A. (登録日: 2024-03-20, 公開日: 2024-05-29)

主引用文献

Omble, A.,Mahajan, S.,Bhoite, A.,Kulkarni, K.
Dishevelled2 activates WGEF via its interaction with a unique internal peptide motif of the GEF.
Commun Biol, 7:543-543, 2024

PubMed 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 (Dvl2) binds and activates WGEF by releasing it from its autoinhibitory state. However, the actual Dvl2 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-Dvl2 interaction to activate the GEF. The residues at P, P, P and P positions of IPM play an important role in stabilizing the WGEF-Dvl2 interaction. Furthermore, MD simulations of modelled Dvl2-WGEF complexes suggest that WGEF-Dvl2 interaction may differ from the reported Dvl2-IPM interactions. Additionally, the apo structure of human Dvl2 shows conformational dynamics different from its IPM peptide bound state, suggesting an induced fit mechanism for the Dvl2-peptide interaction. The current study provides a model for Dvl2 induced activation of WGEF.

PubMed: 38714795
DOI: 10.1038/s42003-024-06194-6

実験手法

X-RAY DIFFRACTION (3 Å)