Abstract
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, and often 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 by Vn using isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) and all-atom molecular dynamics (MD) simulations. The data reveal a hydrophobic groove on the surface of the hemopexin-like (HX) domain of Vn, that is capable of binding phosphatidylcholine (PC). Conformational landscape analyses of multiple, independent MD simulations identify key structural motifs and intermolecular contacts mediating the association of Vn with PC, and show that 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. Collectively, the data establish a comprehensive structural model for Vn association with HDL and provide mechanistic insight into its accumulation within lipid-rich deposits characteristic of age-related pathologies.