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http://dx.doi.org/10.4062/biomolther.2020.234

Conformational Dynamics of Sclerostin-LRP6 Complex Analyzed by HDX-MS  

Jeong, Yejing (School of Pharmacy, Sungkyunkwan University)
Kim, Jinuk (Department of Biological Sciences, Seoul National University)
Choi, Hee-Jung (Department of Biological Sciences, Seoul National University)
Chung, Ka Young (School of Pharmacy, Sungkyunkwan University)
Publication Information
Biomolecules & Therapeutics / v.29, no.5, 2021 , pp. 527-535 More about this Journal
Abstract
Sclerostin (SOST), a regulator of bone formation in osteocytes, inhibits the canonical Wnt signaling by interacting with low-density lipoprotein receptor-related protein 5/6 (LRP5/6) to prevent Wnt binding. Loss-of-function mutations of the SOST gene caused massive bone outgrowth and SOST-null mouse exhibited a high bone density phenotype. Therefore, SOST has been suggested as a promising therapeutic target for osteoporosis. A few previous studies with X-ray crystallography identified the binding interfaces between LRP6 and SOST, but there are limitations in these studies as they used truncated SOST protein or SOST peptide. Here, we analyzed the conformational dynamics of SOST-LRP6 E1E2 complex using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We examined the effect of the C-terminal tail of SOST on LRP6 conformation upon complex formation. HDX-MS analysis suggested a new potential binding interface for the C-terminal region of SOST that was missing from the previous crystal structure of the SOST-LRP6 E1E2 complex.
Keywords
Low-density lipoprotein receptor-related protein 6; Sclerostin; Wnt signaling; HDX-MS;
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