Striking a balance: mapping the structural stability and mechanical and chemical responsiveness of collagen proteins

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Multicellular life is scaffolded by structures that maintain cells in the desired locations and organizations. Conventionally these scaffolds are viewed as rigid, unchanging supports laid down during development and unaltered except by injury or disease. Recent scientific advances are revealing instead that these extracellular scaffolds are highly dynamic, responsive to changes in their local microenvironment and communicating these changes to the cells they support, which in turn modify these scaffolds to adapt to their changed environment. In humans (and all multicellular animals), the main component of these scaffolds is a protein called collagen (from the French "coller" or to glue). At its smallest (molecular) level, this protein has a unique triple helix structure, with three chains twisting around each other to make a long, right-handed helix. Collagen proteins are made inside cells, then assemble into a wide variety of higher-order structures outside cells to form environment-specific scaffolds supporting a diversity of function. For example, collagens form the rope-like structure of tendon, with similar organizations templating the mineralization of bone; they alternatively can form networks that support cells at the periphery of our tissues, separating "inside" from "outside", and networks that form the filtration barrier of the kidney. The rapidly expanding field of mechanobiology is demonstrating that cells respond to the mechanics of their extracellular environment; for example stem cells differentiate into bone vs. fat cells when grown on a stiff vs. soft surface. What is not clear is how the extracellular environment communicates this information to cells. Because of the predominance of collagen (more than ¼ of the protein in our bodies), we aim to understand how collagen senses and communicates mechanical and chemical changes in its local environment. My research group has developed internationally unique skills in collagen characterization, which enable us to probe the mechanical properties of individual collagen proteins. We do this by a combination of single-molecule imaging (using the technique of atomic force microscopy) and single-molecule force spectroscopy (using a new technique of centrifuge force microscopy). We aim to understand how the sequence variability along the length of collagen's triple helix is used to communicate changes in chemical environment (occurring, for example, during secretion from the cell or in biological processes such as bone degradation and cancer metastasis) and mechanical strain (occurring, for example, with every step we take or by cells tugging at their extracellular matrix). Students in my research group gain experimental expertise at the interface of physics and biology, develop communication skills within a diverse research team, and have the opportunity to build international leadership in the fields of mechanobiology and biophysics.