SpeakerDr. Sergey Leikin, Senior Investigator @ NIH, Host: Ian Morgan
Date and LocationWednesday May 11, 2016 11:00am to 12:00pm
Bones derive their strength and elasticity from deposition of hard yet brittle hydroxyapatite mineral into elastic yet soft fibers of collagen triple helices. Mutations that disrupt the structure of collagen helices are responsible for 80-90% of genetic bone fragility and malformations. Hence, our journey toward understanding the latter disorders started from physics of interactions between collagen triple helices and their self-assembly into fibers. Along the way, we determined how the helical structure affects forces between macromolecules not only in collagen fibers but also in nucleic acid assemblies. Trying to understand the temperature dependence of these forces, we discovered that folding of the procollagen precursor of collagen is an uphill climb on a free energy landscape rather than a descent toward a thermodynamically favorable state. Folding of this most abundant vertebrate protein does not conform to the classical Anfinsen’s paradigm of protein folding and presents a major challenge for cells, particularly osteoblasts. These bone-making cells secrete more collagen in a single day than the combined amount of all other proteins they have inside. After years of investigating how disruption of collagen interactions in fibers by collagen mutations causes bone fragility, we found a more pronounced relationship of bone fragility to disruptions in the procollagen folding process. Malformations of the collagen matrix of bone are largely caused by malfunction of osteoblasts in response to procollagen misfolding. The key to treatment of bone pathology and bone engineering might lie not outside but inside the cell. Our subsequent studies of collagen synthesis, processing, trafficking and degradation in osteoblasts produced even more surprises. Misfolding and accumulation of mutant procollagen in Endoplasmic Reticulum (ER) causes cell stress response that is inconsistent with either the conventional unfolded protein response (UPR) or conventional ER overload. It activates trafficking of the misfolded molecules from the ER for degradation in lysosomes via an unusual autophagy pathway. At least in one mouse model of the disorder, variations in the efficiency of this autophagic degradation pathway appear to be responsible for variations in the severity of bone pathology, suggesting potential new targets for therapeutic intervention. The entire process, from collagen precursor folding to its quality control, trafficking, secretion, enzymatic processing, and assembly into collagen fibers turns out to be uniquely interesting and revealing yet poorly understood. We argue that solving this puzzle is crucially important not only for collagen-related diseases that affect bones and other tissues but also for general understanding of cell biology and for many tissue engineering applications.