Mechano-adaptive sensory mechanism of α-catenin under tension.

Koichiro Maki,Sung-Woong Han,Toshio Hakoshima,Shigenobu Yonemura,Taiji Adachi,Yoshinori Hirano

doi:10.1038/srep24878

Koichiro Maki, Sung-Woong Han + Show 4 more

Open Access

https://doi.org/10.1038/srep24878

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Abstract

The contractile forces in individual cells drive the tissue processes, such as morphogenesis and wound healing, and maintain tissue integrity. In these processes, α-catenin molecule acts as a tension sensor at cadherin-based adherens junctions (AJs), accelerating the positive feedback of intercellular tension. Under tension, α-catenin is activated to recruit vinculin, which recruits actin filaments to AJs. In this study, we revealed how α-catenin retains its activated state while avoiding unfolding under tension. Using single-molecule force spectroscopy employing atomic force microscopy (AFM), we found that mechanically activated α-catenin fragment had higher mechanical stability than a non-activated fragment. The results of our experiments using mutated and segmented fragments showed that the key intramolecular interactions acted as a conformational switch. We also found that the conformation of α-catenin was reinforced by vinculin binding. We demonstrate that α-catenin adaptively changes its conformation under tension to a stable intermediate state, binds to vinculin, and finally settles into a more stable state reinforced by vinculin binding. Our data suggest that the plastic characteristics of α-catenin, revealed in response to both mechanical and biochemical cues, enable the functional-structural dynamics at the cellular and tissue levels.

Highlights

A combination of contractile forces in individual cells drives tissue dynamics such as morphogenesis[1,2,3] and wound healing[4]
We investigated the mechanical behaviors of mutated, segmented, and vinculin-bound α -catenin using single-molecule force spectroscopy (SMFS)[25,26,27] employing atomic force microscopy (AFM)
The mutant fragment, in which the autoinhibiting MI/MII– MIII interaction is disrupted, behaved as an activated α -catenin that interacts with vinculin under no tension (Supplementary Figure 1)

Summary

Introduction

A combination of contractile forces in individual cells drives tissue dynamics such as morphogenesis[1,2,3] and wound healing[4]. AJs balance the intercellular tensions by the adaptive assembly of the cytoskeletal actin filaments[7,8,9,10] In this mechano-adaptive mechanism, α -catenin, a tension-sensing component of AJs, is critical regulator of vinculin binding[11,12,13], which recruits another actin filament to AJ14,15. The molecular and cellular study of Yonemura et al.[16] has revealed that α -catenin under intercellular tension exposes the cryptic vinculin binding site (VBS). Thereby, the MI/MII–MIII interaction holds the key to the mechanical activation of α -catenin, recruiting vinculin under tension. The most significant question is how does α -catenin, one of the tension-sensing proteins, retain its activated state while avoiding the successive unfolding under denaturing tension

Methods

Results

Conclusion