Role Of Vitronectin In The Formation Of Lipid-Protein Aggregates In Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a devastating disease characterized by the formation of protein-lipid deposits that build up in the extracellular space below the basal membrane of the retinal pigment epithelium. This leads to impaired metabolic exchange, retina degeneration, and ultimately, vision loss. Recent studies showed that AMD deposits are made up of µm-sized spherical particles (spherules) composed of a cholesterol-rich lipid core coated with a shell of hydroxyapatite, the mineralized form of calcium phosphate, and a final top coat of protein. The extracellular protein Vitronectin (Vn) is a major component of the AMD proteome and is enriched on the spherule surface. Vn is also known to regulate a plethora of physiological processes, including lipid metabolism and the immune response, through its interactions with lipids, cholesterol, and various proteins. Nevertheless, little is known about the biophysical basis for its functions and for its role in AMD. Here we describe the structure of the major C-terminal domain of Vn, we characterize its interaction with calcium, phosphate, lipid and hydroxyapatite, and we propose a Vn-coordinated mechanism for AMD spherule formation. Using solution NMR, solid-state NMR and other biophysical and biochemical techniques, we characterize the binding thermodynamics and associated changes in protein structure and dynamics. Our results provide the first quantitative and site-specific insights into the role of Vn in AMD spherule formation, and provide an avenue for the development of small molecule inhibitors of macular degeneration.