Calcium and hydroxyapatite binding site of human vitronectin provides insights to abnormal deposit formation. Proc Natl Acad Sci U S A 2020 Aug 04;117(31):18504-18510
Date
07/24/2020Pubmed ID
32699145Pubmed Central ID
PMC7414086DOI
10.1073/pnas.2007699117Scopus ID
2-s2.0-85089166480 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
The human blood protein vitronectin (Vn) is a major component of the abnormal deposits associated with age-related macular degeneration, Alzheimer's disease, and many other age-related disorders. Its accumulation with lipids and hydroxyapatite (HAP) has been demonstrated, but the precise mechanism for deposit formation remains unknown. Using a combination of solution and solid-state NMR experiments, cosedimentation assays, differential scanning fluorimetry (DSF), and binding energy calculations, we demonstrate that Vn is capable of binding both soluble ionic calcium and crystalline HAP, with high affinity and chemical specificity. Calcium ions bind preferentially at an external site, at the top of the hemopexin-like (HX) domain, with a group of four Asp carboxylate groups. The same external site is also implicated in HAP binding. Moreover, Vn acquires thermal stability upon association with either calcium ions or crystalline HAP. The data point to a mechanism whereby Vn plays an active role in orchestrating calcified deposit formation. They provide a platform for understanding the pathogenesis of macular degeneration and other related degenerative disorders, and the normal functions of Vn, especially those related to bone resorption.
Author List
Shin K, Kent JE, Singh C, Fujimoto LM, Yu J, Tian Y, Im W, Marassi FMAuthors
Francesca M. Marassi PhD Chair, Professor in the Biophysics department at Medical College of WisconsinKyungsoo Shin PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Binding SitesCalcium
Durapatite
Humans
Macular Degeneration
Protein Binding
Vitronectin
