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

Emma-Ruoqi Xu, Emily E. Blythe, Gerhard Fischer and  Marko Hyvönen

Journal of Biological Chemistry, 292:12516-12527, 2017
Pubmed ID: 28584056
PDB coordinates: 5NIR (3D view), 5NB8 (3D view)


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.

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