Structural model of the blood protein vitronectin bound to lipid and HDL

Vitronectin (Vn) is a multifunctional blood glycoprotein involved in cell adhesion and migration, blood coagulation, and inflammation. It is a component of the high-density lipoprotein (HDL) proteome also found associated with the calcified, lipid-rich, protein deposits that are a hallmark of age-related macular degeneration, Alzheimer's disease, atherosclerosis and other aging-related diseases. Here we explored the molecular basis for lipid binding and HDL association by Vn. Using nuclear magnetic resonance (NMR) and all-atom molecular dynamics (MD) simulations, we identify a hydrophobic groove on the surface of the Vn hemopexin-like (HX) domain, that is capable of binding phospholipids. Key residues mediate the association of VnHX with phosphatidylcholine (PC) via hydrophobic and polar contacts. Lipid binding is guided by interactions with positively charged and hydrophobic residues that organize the lipids in a tail-to-tail bilayer-like arrangement within the groove. MD simulations of PC-bound VnHX combined with an MD structural model of discoidal HDL, show that VnHX associates with HDL in a lipid-mediated manner and at the exposed edge of the discoidal HDL lipoparticle where the terminal helices of the scaffolding protein ApoA1 flip away. Collectively, the data establish a comprehensive structural model for Vn association with PC and HDL. They expand the range of protein-lipid interactions observed within the structurally and functionally diverse collection of HDL particles.