Hinge sites in the lipid transfer channel modulate function of the yeast bridge-like transfer protein Vps13

Abstract Vps13 transporters are large, rod-shaped proteins that mediate the bulk transfer of lipids between intracellular membranes via a hydrophobic channel formed by multiple “repeating beta-groove” (RBG) domains. Gain-of-function mutants in yeast Vps13 bypass the need for phospholipid trafficking by the endoplasmic reticulum-mitochondrion contact site complex ERMES. This work shows these same mutants can partially compensate for defects in lipid transfer at a different membrane contact site, suggesting that these VPS13 alleles encode a protein that is more efficient than wild type Vps13 at lipid transfer. The gain-of-function mutations map to similar positions on different RBG repeats within the predicted Vps13 structure. Computational modeling of the structural dynamics of individual RBG repeats indicates that these mutations are biased to regions that act as hinges within the protein. We propose that lipid transport by Vps13 involves cycling between conformational states and that these mutants increase lipid transport by altering the dynamics of this conformational shift.