Dimerization Interface of Osteoprotegerin Revealed by Hydrogen-deuterium Exchange Mass Spectrometry
Author
Xiao, Yiming; Li, Miaomiao; Larocque, Rinzhi; Zhang, Fuming; Malhotra, Anju; Chen, Jianle; Linhardt, Robert J.; Konermann, Lars; Xu, DingOther Contributors
Date Issued
2018-01-01Subject
Biology; Chemistry and chemical biology; Chemical and biological engineering; Biomedical engineeringDegree
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CC BY : this license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. Credit must be given to the authors and the original work must be properly cited.; Attribution 3.0 United StatesFull 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.Metadata
Show full item recordAbstract
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.Department
The Linhardt Research Labs.; The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS);Publisher
ElsevierRelationships
The Linhardt Research Labs Online Collection; Rensselaer Polytechnic Institute, Troy, NY; Journal of Biological Chemistry; https://harc.rpi.edu/;Access
CC BY — Creative Commons Attribution; A full text version is available in DSpace@RPI; Open Access;Collections
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