Osteocalcin is the most abundant noncollagenous protein in bone1, and its concentration in serum is closely linked to bone metabolism and serves as a biological marker for the clinical assessment of bone disease2. Although its precise mechanism of action is unclear, osteocalcin influences bone mineralization3,4, in part through its ability to bind with high affinity to the mineral component of bone, hydroxyapatite5. In addition to binding to hydroxyapatite, osteocalcin functions in cell signalling and the recruitment of osteoclasts6 and osteoblasts7, which have active roles in bone resorption and deposition, respectively. Here we present the X-ray crystal structure of porcine osteocalcin at 2.0 Å resolution, which reveals a negatively charged protein surface that coordinates five calcium ions in a spatial orientation that is complementary to calcium ions in a hydroxyapatite crystal lattice. On the basis of our findings, we propose a model of osteocalcin binding to hydroxyapatite and draw parallels with other proteins that engage crystal lattices.
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We thank A. Viinberg for assistance with purification; M. Pereira and R. Ghirlando for help with sedimentation equilibrium data acquisition and data analysis, respectively; and W.-C. Hon for comments on the manuscript. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences. This work was supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada.
The authors declare that they have no competing financial interests.
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Hoang, Q., Sicheri, F., Howard, A. et al. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature 425, 977–980 (2003). https://doi.org/10.1038/nature02079
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