Calcium and hydroxyapatite binding site of human vitronectin provides insights to abnormal deposit formation.
NMR
deposit
drusen
macular degeneration
solid state
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
04 08 2020
04 08 2020
Historique:
pubmed:
24
7
2020
medline:
2
10
2020
entrez:
24
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32699145
pii: 2007699117
doi: 10.1073/pnas.2007699117
pmc: PMC7414086
doi:
Substances chimiques
Vitronectin
0
Durapatite
91D9GV0Z28
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18504-18510Subventions
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118186
Pays : United States
Organisme : CIHR
Pays : Canada
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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