Regulation of titin elasticity
Titin is the largest protein in the human proteome. It is responsible for the passive elasticity of cardiac and skeletal muscle. Titin is the paradigmatic example of a protein that works under mechanical load. We have been studying titin for many years now. We pioneered the concept that Ig domains in titin unfold and refold during titin activity. In our recent article in Cell, we described a new form of molecular memory that allows titin to set its elasticity according to the redox state of myocytes. This new mechanism is based on the posttranslational modification of cryptic residues that become exposed after mechanical unfolding of Ig domains. Similar mechanisms may account for the fact that stretching increases elasticity, for instance after a yoga session. We have also determined that disulfide formation and isomerization are possible in many Ig domains in titin, which provides another checkpoint to control the elasticity of titin. Very clearly, titin is a mechanical computer that outputs the optimized elasticity after integrating multitude of intra and extracellular signals. We are just beginning to understand how titin really works. We are currently implementing tools that can simulate the elastic behavior of titin, and how posttranslational modifications or disease-linked mutations affect the elastic output of titin, our amazing molecular computer.