Structural basis of the human Scribble-Vangl2 association in health and disease

Area of Science:

• Cell Biology
• Developmental Biology
• Structural Biology

Background:

• Scribble is a key cell polarity regulator implicated in cancer and development.
• Mutations in Scribble are linked to neural tube defects, often attributed to impaired Vangl2 interaction.

Purpose of the Study:

• To elucidate the structural basis of Scribble's interaction with Vangl2.
• To investigate the impact of neural tube defect-associated mutations on Scribble's binding capabilities.

Main Methods:

• X-ray crystallography to determine the structure of Scribble PDZ domains bound to Vangl2 peptide.
• Analysis of mammalian neural tube defect mutations in the context of Scribble structure and Vangl2 binding.

Main Results:

• Crystal structures reveal Scribble PDZ domains 1-3 bind the Vangl2 C-terminal motif.
• Mutations distal to the binding groove disrupt Vangl2 binding and interactions with other signaling partners.
• These mutations act as broad-spectrum loss-of-function mutants.

Conclusions:

• Scribble's interaction with Vangl2 is mediated by its PDZ domains.
• Neural tube defect mutations in Scribble can disrupt multiple protein interactions, leading to a global loss of function.
• The findings provide a mechanistic understanding of Scribble-associated developmental defects beyond Vangl2-specific interactions.