Vitronectin, the major regulator of age-related macular degeneration

Age-related macular degeneration (AMD) is one of the leading causes of blindness. In AMD, the transfer of nutrients and waste between choroid capillary and retinal pigment epithelium is impaired by the build-up of insoluble deposits leading to progressive photoreceptor atrophy. The AMD deposits contain µm-sized spherical particles (i.e., spherules) with a cholesterol-rich lipid core coated by hydroxyapatite (Ca5(PO4)3(OH)). Spherules often recruit proteins to form a top layer, with different proteins forming morphologically distinct deposits. The blood protein vitronectin (Vn) is one of these proteins and, notably, completely encapsulates both the fully and partially formed spherules, indicating a structural role in their formation. In support, Vn has long been associated with the disease proteome. However, the exact role of Vn remains challenging to discern, as Vn binds to many biomolecules to regulate a plethora of physiological processes, including the immune system and lipid metabolism. Here we use a multidisciplinary biophysical and structural approach to characterize the interactions of Vn with AMD spherule constituents to characterize the associated thermodynamics, conformational changes, and binding mode. We also describe the influence of Vn and other known modulators on hydroxyapatite and AMD proto-spherule formation. Our results illustrate the structural and functional role of Vn in AMD spherule formation with insight at the molecular level with site-specificity to offer a platform for further therapeutic development.