MECHANOSENSITIVE HEART FUNCTIONS OF aT-CATENIN AND CARDIAC TITIN

Abstract

αE-catenin play a crucial mechanosensitive role in its interaction with vinculin. Interestingly, the middle-1 domain in αT-catenin, which is unique to the heart (and testis), contains a sequence that is highly similar to the vinculin binding site in αE-catenin. However, it is unclear if this sequence is a VBS. Assuming that it binds vinculin, it is not known if this interaction requires mechanical activation, nor the binding affinity when under force. Beside the mechanosensitive function of αT-catenin, the mechanisms involved in regulating passive tension are also crucial in the heart. The I-band region of titin N2B isoform contains two largely unstructured domains: N2B-Us (which is unique to the heart) and PEVK, which are highly flexible and believed to play a key role in passive tension regulation. However, the force-responses of these two domains remained poorly understood. Using magnetic tweezers, I investigated the force responses of the three middle domains in αT-catenin, N2B-Us, and PEVK within 1-40 pN. Remarkably, the results provided important new insights into the mechanosensitive functions of αT-catenin in regulating cell-cell adhesion, and the important roles that N2B domain plays in regulating passive tension, which have broad implications in diastolic and cardiac trophic functions.