Dimerization Interface of Osteoprotegerin Revealed by Hydrogen-deuterium Exchange Mass Spectrometry
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Authors
Xiao, Yiming
Li, Miaomiao
Larocque, Rinzhi
Zhang, Fuming
Malhotra, Anju
Chen, Jianle
Linhardt, Robert J.
Konermann, Lars
Xu, Ding
Issue Date
2018-01-01
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Alternative Title
Abstract
Previous structural studies of osteoprotegerin (OPG), a crucial negative regulator of bone remodeling and osteoclastogenesis, were mostly limited to the N-terminal ligand-binding domains. It is now known that the three C-terminal domains of OPG also play essential roles in its function by mediating OPG dimerization, OPG-heparan sulfate (HS) interactions, and formation of the OPG-HS-receptor activator of nuclear factor κB ligand (RANKL) ternary complex. Employing hydrogen-deuterium exchange MS methods, here we investigated the structure of full-length OPG in complex with HS or RANKL in solution. Our data revealed two noteworthy aspects of the OPG structure. First, we found that the interconnection between the N- and C-terminal domains is much more rigid than previously thought, possibly because of hydrophobic interactions between the fourth cysteine-rich domain and the first death domain. Second, we observed that two hydrophobic clusters located in two separate C-terminal domains directly contribute to OPG dimerization, likely by forming a hydrophobic dimerization interface. Aided by site-directed mutagenesis, we further demonstrated that an intact dimerization interface is essential for the biological activity of OPG. Our study represents an important step toward deciphering the structure-function relationship of the full-length OPG protein.
Description
Journal of Biological Chemistry, 293, 17523–17535
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Full Citation
Dimerization Interface of Osteoprotegerin Revealed by Hydrogen-deuterium Exchange Mass Spectrometry Y. Xiao, M. Li, R. Larocque, F. Zhang, A. Malhotra, J. Chen, R. J. Linhardt, L. Konermann, D. Xu, Journal of Biological Chemistry, 293, 17523–17535, 2018.
Publisher
Elsevier
Terms of Use
Journal
Volume
Issue
PubMed ID
DOI
ISSN
1083351X
219258
219258