TCB Publications - Abstract

Samantha Barrick, Jing Li, Xinyu Kong, Alokananda Ray, Emad Tajkhorshid, and Deborah Leckband. Salt bridges gate α-catenin activation at intercellular junctions. Molecular Biology of the Cell, 29:111-122, 2018. (PMC: PMC5909925)

BARR2018-ET Cadherin complexes transduce force fluctuations at junctions to activate signals that reinforce stressed intercellular contacts. $\alpha$-Catenin is an identified force transducer within cadherin complexes that is autoinhibited under low tension. Increased force triggers a conformational change that exposes a cryptic site for the actin-binding protein vinculin. This study tested predictions that salt bridges within the force-sensing core modulate $\alpha$-catenin activation. Studies with a fluorescence resonance energy transfer (FRET)-based $\alpha$-catenin conformation sensor demonstrated that the salt-bridge mutations R551A and D503N each enhance $\alpha$-catenin activation in live cells, but R551A has a greater impact. Under dynamic force loading at reannealing cell-cell junctions, the R551A mutant bound more vinculin than wild-type $\alpha$- catenin. In vitro binding measurements quantified the impact of the R551A mutation on the free energy difference between the active and autoinhibited $\alpha$-catenin conformers. A two-microsecond, constant- force steered molecular dynamics simulation of the core force-sensing region suggested how the salt-bridge mutants alter the $\alpha$-catenin conformation, and identified a novel load-bearing salt bridge. These results reveal key structural features that determine the force-transduction mechanism and the force sensitivity of this crucial nanomachine.

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