biostudies-literatureAdlakha JAligning Science Across Parkinson'sChina Scholarship CouncilAligning Science Across Parkinson’sNational Institutes of HealthHealth Effects InstituteNIGMS NIH HHSNIH HHSe202202030https://www.ebi.ac.uk/biostudies/studies/S-EPMC8978259biostudies-literatureUnknown221(5)VPS13 proteins are proposed to function at contact sites between organelles as bridges for lipids to move directionally and in bulk between organellar membranes. VPS13s are anchored between membranes via interactions with receptors, including both peripheral and integral membrane proteins. Here we present the crystal structure of VPS13s adaptor binding domain (VAB) complexed with a Pro-X-Pro peptide recognition motif present in one such receptor, the integral membrane protein Mcp1p, and show biochemically that other Pro-X-Pro motifs bind the VAB in the same site. We further demonstrate that Mcp1p and another integral membrane protein that interacts directly with human VPS13A, XK, are scramblases. This finding supports an emerging paradigm of a partnership between bulk lipid transport proteThe Journal of cell biologyStructural and biochemical insights into lipid transport by VPS13 proteins.PMC8978259R35 GM131715ASAP-000580R35GM131715P30 GM124165DE-AC02-06CH11357S10 OD021527S10OD021527Hong ZAdlakha JReinisch KMLi PfalseStructural and biochemical insights into lipid transport by VPS13 proteins.VPS13 proteins are proposed to function at contact sites between organelles as bridges for lipids to move directionally and in bulk between organellar membranes. VPS13s are anchored between membranes via interactions with receptors, including both peripheral and integral membrane proteins. Here we present the crystal structure of VPS13s adaptor binding domain (VAB) complexed with a Pro-X-Pro peptide recognition motif present in one such receptor, the integral membrane protein Mcp1p, and show biochemically that other Pro-X-Pro motifs bind the VAB in the same site. We further demonstrate that Mcp1p and another integral membrane protein that interacts directly with human VPS13A, XK, are scramblases. This finding supports an emerging paradigm of a partnership between bulk lipid transport prote2022-01-01T00:00:00Z2022 Jun2026-05-30T20:57:42.294Z2025-04-04T10:02:22.967ZS-EPMC89782593535742210.1083/jcb.202202030