1. Department of Biochemistry, Faculty of Health Science, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
2. Microstar Biotech Inc., 7 Innovation Drive, Flamborough, Ontario L9H 7H9, Canada
3. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
4. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
5. Department of Biological, Chemical and Physical Sciences, Illinois Institute Technology, Chicago, Illinois 60616, USA

Correspondence to: Daniel S. C. Yang¹ Correspondence and requests for materials should be addressed to D.S.C.Y.. (Email: yang@mcmaster.ca). The coordinates of the structure are deposited in the Protein Data Bank under accession code 1Q8H.

Abstract

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 mineralization^{3, 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.