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
American Society for Biochemistry and Molecular Biology Inc.
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Hyvonen, M., Xu, E., Blythe, E., & Fischer, G. (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 12516-12527. https://doi.org/10.1074/jbc.M117.788992
Bone morphogenetic proteins (BMPs) are secreted growth factors that promote differentiation processes in embryogenesis and tissue development. Regulation of BMP signalling involves binding to a variety of extracellular proteins, among which are many von Willebrand factor C (vWC) domain-containing proteins. While 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 analysed 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.
bone morphogenetic protein (BMP), collagen, crystal structure, extracellular matrix protein, protein-protein interaction, signaling, CCN proteins, vWC domain
This work was supported by Cambridge Overseas Trust and China Scholarship Council through a postgraduate scholarship to E-R. X.
External DOI: https://doi.org/10.1074/jbc.M117.788992
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264963