Dimerization interface of osteoprotegerin revealed by hydrogen– Deuterium exchange mass spectrometry

Yiming Xiao, Miaomiao Li, Rinzhi Larocque, Fuming Zhang, Anju Malhotra, Jianle Chen, Robert J. Linhardt, Lars Konermann, Ding Xu

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 ĸB 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.

Original languageEnglish
Pages (from-to)17523-17535
Number of pages13
JournalJournal of Biological Chemistry
Issue number45
StatePublished - 2018
Externally publishedYes


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