Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• VPS13 family proteins facilitate inter-organelle lipid transfer via membrane conduits.
• Mutations in human VPS13 genes cause inherited disorders.
• VPS13 proteins possess conserved domains, including the Vps13 adaptor-binding (VAB) domain.

Purpose of the Study:

• To investigate the role of the pleckstrin homology (PH) domain in VPS13A function.
• To determine the interaction between VPS13A and XK scramblase.
• To elucidate the molecular basis of VPS13A disease and McLeod syndrome.

Main Methods:

• Utilized Alphafold modeling to predict the VPS13A-XK interaction surface.
• Generated mutations in the predicted interaction region.
• Analyzed protein complex formation and co-localization.

Main Results:

• The C-terminal PH domain of VPS13A is essential for complex formation and co-localization with XK scramblase.
• Mutations in the PH domain disrupt the VPS13A-XK interaction.
• Patient-derived VPS13A mutations truncate the PH domain.

Conclusions:

• The VPS13A-XK complex, mediated by the PH domain, is critical for cellular function.
• Disruption of the VPS13A-XK complex is implicated in the pathogenesis of VPS13A disease and McLeod syndrome.