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Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2

Xu, Emma-Ruoqi and Blythe, Emily E. and Fischer, Gerhard and Hyvönen, Marko (2017) Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2. Journal of Biological Chemistry, 292 (30). pp. 12516-12527. ISSN 0021-9258. PMCID PMC5535026. https://resolver.caltech.edu/CaltechAUTHORS:20170828-135538047

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Abstract

Bone morphogenetic proteins (BMPs) are secreted growth factors that promote differentiation processes in embryogenesis and tissue development. Regulation of BMP signaling involves binding to a variety of extracellular proteins, among which are many von Willebrand factor C (vWC) domain-containing proteins. Although the crystal structure of the complex of crossveinless-2 (CV-2) vWC1 and BMP-2 previously revealed one mode of the vWC/BMP-binding mechanism, other vWC domains may bind to BMP differently. Here, using X-ray crystallography, we present for the first time structures of the vWC domains of two proteins thought to interact with BMP-2: collagen IIA and matricellular protein CCN3. We found that these two vWC domains share a similar N-terminal fold that differs greatly from that in CV-2 vWC, which comprises its BMP-2-binding site. We analyzed the ability of these vWC domains to directly bind to BMP-2 and detected an interaction only between the collagen IIa vWC and BMP-2. Guided by the collagen IIa vWC domain crystal structure and conservation of surface residues among orthologous domains, we mapped the BMP-binding epitope on the subdomain 1 of the vWC domain. This binding site is different from that previously observed in the complex between CV-2 vWC and BMP-2, revealing an alternative mode of interaction between vWC domains and BMPs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1074/jbc.M117.788992DOIArticle
http://www.jbc.org/content/292/30/12516PublisherArticle
http://www.jbc.org/cgi/content/full/M117.788992/DC1PublisherSupplemental Material
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535026/PubMed CentralArticle
ORCID:
AuthorORCID
Xu, Emma-Ruoqi0000-0001-7300-3868
Blythe, Emily E.0000-0001-6363-2644
Fischer, Gerhard0000-0001-9861-1528
Hyvönen, Marko0000-0001-8683-4070
Additional Information:© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Received April 4, 2017. Revision received May 18, 2017. First Published on June 5, 2017. This work was supported by Cambridge Overseas Trust and China Scholarship Council through a postgraduate scholarship (to E.-R. X.). The authors declare that they have no conflicts of interest with the contents of this article. We thank Katharina Ravn for the production of BMP-2 and Dr. May Marsh for help with crystallization. We are grateful for access to and support at the X-ray crystallographic and Biophysics facilities at the Department of Biochemistry. We thank the Diamond Light Source and the beamline staff for access to beamline i02, i04-1 and i24 (proposals mx6886 and mx7141, respectively), and ESRF (European Synchrotron Radiation Facility) and their beamline staff for access to beamline BM14.
Funders:
Funding AgencyGrant Number
Cambridge Overseas TrustUNSPECIFIED
China Scholarship CouncilUNSPECIFIED
Issue or Number:30
PubMed Central ID:PMC5535026
Record Number:CaltechAUTHORS:20170828-135538047
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170828-135538047
Official Citation:Emma-Ruoqi Xu, Emily E. Blythe, Gerhard Fischer, and Marko Hyvönen Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2 J. Biol. Chem. 2017 292: 12516-. doi:10.1074/jbc.M117.788992
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:80855
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Aug 2017 21:05
Last Modified:03 Oct 2019 18:35

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