Functional Structural Biology of Noncollagenous Bone Matrix Proteins

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Bone is a complex inorganic-organic composite with critical mechanical and physiological implications. Despite being minor components, noncollagenous matrix proteins (NCPs) play regulatory roles and impart cohesion to the calcified organic matrix. While transgenic mouse models and cell culture studies have allowed substantial progress in understanding the overall biological activity of NCPs and their contribution to building and maintaining bone, how their molecular structure mediates mineral deposition is still subject of debate. Much of the current information derives from in silico predictions and artificial test tube assays. While extremely informative, such experimental and theoretical studies on protein­mineral relationships are at best “crude approximations” of what really happens at the molecular scale in the complex biological environment of the body. There is therefore a need to validate results from such studies under more physiologically- relevant conditions. Towards this objective, this proposal will exploit an integrative ‘functional structural biology’ approach to understand how molecular structure, motifs and domains define the relationship of NCPs to the mineral phase.