Calcium-induced environmental adaptability of the blood protein vitronectin

Author:

Tian Ye,Shin Kyungsoo,Aleshin Alexander E.,Im Wonpil,Marassi Francesca M.ORCID

Abstract

AbstractThe adaptability of proteins to their work environments is fundamental for cellular life. Here we describe how the hemopexin-like (HX) domain of the multifunctional blood glycoprotein vitronectin (Vn) binds Ca2+ to adapt to excursions of temperature and shear stress. Using X-ray crystallography and molecular dynamics (MD) simulations, nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSF), we describe how Ca2+ and its flexible hydration shell enable the protein to perform conformational changes, that relay beyond the Ca2+ binding site to alter the number of polar contacts and confer conformational stability. By means of mutagenesis, we identify key residues that cooperate with Ca2+ to promote protein stability, and we show that Ca2+ association confers protection against shear stress, a property that provides conformational advantage for proteins that circulate in the vasculature like Vn. The data reveal a mechanism of adaptation.Significance StatementThe protein vitronectin (Vn) plays important roles in cell adhesion and migration, bone remodeling and immunity. It circulates in blood, but it is also found in the extracellular matrix, and it accumulates with plaques associated with age-related macular degeneration, Alzheimer’s disease, atherosclerosis and other degenerative disorders. Vn is a calcium-binding protein, and here, we show that calcium helps Vn alter its structure in response to diverse environmental conditions. The results shed light on the way in which Vn adapts to its surroundings. This structural knowledge is important for the development of diagnostic, preventive or therapeutic approaches.

Publisher

Cold Spring Harbor Laboratory

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