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8wwr

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Crystal structure of apo human dishevelled 2 (Dvl2) PDZ domain

Structural highlights

8wwr is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.75Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DVL2_HUMAN Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Promotes internalization and degradation of frizzled proteins upon Wnt signaling. Plays a role both in canonical and non-canonical Wnt signaling. Plays a role in the signal transduction pathways mediated by multiple Wnt genes (By similarity).^[1]

Publication Abstract from PubMed

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(PDZ)) binds and activates WGEF by releasing it from its autoinhibitory state. However, the actual Dvl2(PDZ) 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(PDZ) interaction to activate the GEF. The residues at P(2), P(0), P(-2) and P(-3) positions of IPM play an important role in stabilizing the WGEF(pep)-Dvl2(PDZ) interaction. Furthermore, MD simulations of modelled Dvl2(PDZ)-WGEF(IPM peptide) complexes suggest that WGEF-Dvl2(PDZ) interaction may differ from the reported Dvl2(PDZ)-IPM interactions. Additionally, the apo structure of human Dvl2(PDZ) shows conformational dynamics different from its IPM peptide bound state, suggesting an induced fit mechanism for the Dvl2(PDZ)-peptide interaction. The current study provides a model for Dvl2 induced activation of WGEF.

Dishevelled2 activates WGEF via its interaction with a unique internal peptide motif of the GEF.,Omble A, Mahajan S, Bhoite A, Kulkarni K Commun Biol. 2024 May 7;7(1):543. doi: 10.1038/s42003-024-06194-6. PMID:38714795^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhang Y, Appleton BA, Wiesmann C, Lau T, Costa M, Hannoush RN, Sidhu SS. Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nat Chem Biol. 2009 Apr;5(4):217-9. Epub 2009 Mar 1. PMID:19252499 doi:10.1038/nchembio.152
↑ 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. 2024 May 7;7(1):543. PMID:38714795 doi:10.1038/s42003-024-06194-6