Salt bridges gate α-catenin activation at intercellular junctions.

Area of Science:

• Cell biology
• Biophysics
• Structural biology

Background:

• Cadherin complexes mediate cell-cell adhesion and signal transduction.
• Alpha-catenin (α-catenin) acts as a force transducer within these complexes, regulated by mechanical tension.
• Force-induced conformational changes in α-catenin expose binding sites for proteins like vinculin.

Purpose of the Study:

• To investigate the role of salt bridges in the force-sensing core of α-catenin.
• To determine how specific mutations affecting salt bridges modulate α-catenin activation and vinculin binding.
• To elucidate the structural mechanisms underlying α-catenin's force sensitivity.

Main Methods:

• Utilized a Förster resonance energy transfer (FRET)-based α-catenin conformation sensor in live cells.
• Performed dynamic force loading experiments at reannealing cell-cell junctions.
• Conducted in vitro binding assays and steered molecular dynamics simulations.

Main Results:

• Salt bridge mutations (R551A and D503N) enhanced α-catenin activation, with R551A showing a greater effect.
• The R551A mutant exhibited increased vinculin binding under dynamic force loading.
• Molecular dynamics simulations identified a novel load-bearing salt bridge and provided insights into conformational changes.

Conclusions:

• Salt bridges within α-catenin are critical determinants of its force-transduction mechanism.
• Specific mutations can tune the force sensitivity and activation of α-catenin.
• These findings reveal structural features essential for the mechanical regulation of cell adhesion.