Abstract

Cadherin complexes transduce force fluctuations at junctions to activate signals that reinforce stressed intercellular contacts. ?-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 ?-catenin activation. Studies with a fluorescence resonance energy transfer (FRET)-based ?-catenin conformation sensor demonstrated that each of the salt-bridge mutations R551A and D503N enhances ?-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 ?-catenin. In vitro binding measurements quantified the impact of the R551A mutation on the free-energy difference between the active and autoinhibited ?-catenin conformers. A 2-?s constant-force, steered molecular dynamics simulation of the core force-sensing region suggested how the salt-bridge mutants alter the ?-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.

Original languageEnglish (US)
Pages (from-to)111-122
Number of pages12
JournalMolecular biology of the cell
Volume29
Issue number2
DOIs
StatePublished - Jan 15 2018

Fingerprint

Catenins
Intercellular Junctions
Salts
Vinculin
Cadherins
Microfilament Proteins
Fluorescence Resonance Energy Transfer
Mutation
Weight-Bearing
Molecular Dynamics Simulation
Transducers

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Salt bridges gate ?-catenin activation at intercellular junctions. / Barrick, Samantha; Li, Jing; Kong, Xinyu; Ray, Alokananda; Tajkhorshid, Emad; Leckband, Deborah.

In: Molecular biology of the cell, Vol. 29, No. 2, 15.01.2018, p. 111-122.

Research output: Contribution to journalArticle

Barrick, Samantha ; Li, Jing ; Kong, Xinyu ; Ray, Alokananda ; Tajkhorshid, Emad ; Leckband, Deborah. / Salt bridges gate ?-catenin activation at intercellular junctions. In: Molecular biology of the cell. 2018 ; Vol. 29, No. 2. pp. 111-122.
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