Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.234
Conformational Dynamics of Sclerostin-LRP6 Complex Analyzed by HDX-MS
Yejing Jeong1, Jinuk Kim2, Hee-Jung Choi2,* and Ka Young Chung1,*
1School of Pharmacy, Sungkyunkwan University, Suwon 16419,
2Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
*E-mail: choihj@snu.ac.kr (Choi HJ), kychung2@skku.edu (Chung KY)
Tel: +82-2-880-6605 (Choi HJ), +82-31-290-7787 (Chung KY)
Fax: +82-2-872-1993 (Choi HJ), +82-31-292-8800 (Chung KY)
Received: December 29, 2020; Revised: March 19, 2021; Accepted: March 22, 2021; Published online: April 9, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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. HDXMS 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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