Abstract
The adaptability of proteins to their work environments is fundamental for cellular life. Here, we describe how the hemopexin-like domain of the multifunctional blood glycoprotein vitronectin binds Ca(2+) to adapt to excursions of temperature and shear stress. Using X-ray crystallography, molecular dynamics simulations, NMR, and differential scanning fluorimetry, we describe how Ca(2+) and its flexible hydration shell enable the protein to perform conformational changes that relay beyond the calcium-binding site and alter the number of polar contacts to enhance conformational stability. By means of mutagenesis, we identify key residues that cooperate with Ca(2+) to promote protein stability, and we show that calcium association confers protection against shear stress, a property that is advantageous for proteins that circulate in the vasculature, like vitronectin.