title: Structural Determinants of the Mechanical Stability of α-Catenin.
abstract: α-Catenin plays a crucial role in cadherin-mediated adhesion by binding to β-catenin, F-actin, and vinculin, and its dysfunction is linked to a variety of cancers and developmental disorders. As a mechanotransducer in the cadherin complex at intercellular adhesions, mechanical and force-sensing properties of α-catenin are critical to its proper function. Biochemical data suggest that α-catenin adopts an autoinhibitory conformation, in the absence of junctional tension, and biophysical studies have shown that α-catenin is activated in a tension-dependent manner that in turn results in the recruitment of vinculin to strengthen the cadherin complex/F-actin linkage. However, the molecular switch mechanism from autoinhibited to the activated state remains unknown for α-catenin. Here, based on the results of an aggregate of 3 μs of molecular dynamics simulations, we have identified a dynamic salt-bridge network within the core M region of α-catenin that may be the structural determinant of the stability of the autoinhibitory conformation. According to our constant-force steered molecular dynamics simulations, the reorientation of the MII/MIII subdomains under force may constitute an initial step along the transition pathway. The simulations also suggest that the vinculin-binding domain (subdomain MI) is intrinsically much less stable than the other two subdomains in the M region (MII and MIII). Our findings reveal several key insights toward a complete understanding of the multistaged, force-induced conformational transition of α-catenin to the activated conformation.
authors.affiliation: From the Department of Biochemistry, Center for Biophysics and Computational Biology, Beckman Institute for Advanced Science and Technology, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
authors.forename: Jillian
authors.initials: J
authors.lastname: Newhall
authors.affiliation: the Princess Margaret Cancer Centre and.
authors.forename: Noboru
authors.initials: N
authors.lastname: Ishiyama
authors.affiliation: the Department of Acute Pulmonary Care, Feinberg College of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Cara
authors.initials: C
authors.lastname: Gottardi
authors.affiliation: the Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada, and.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ikura
authors.affiliation: From the Department of Biochemistry, Center for Biophysics and Computational Biology, Beckman Institute for Advanced Science and Technology, and Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, leckband@illinois.edu.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Leckband
authors.affiliation: From the Department of Biochemistry, Center for Biophysics and Computational Biology, Beckman Institute for Advanced Science and Technology, and emad@life.illinois.edu.
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
mesh_terms: D000595:Amino Acid Sequence; D002448:Cell Adhesion; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051178:alpha Catenin / Q000737:chemistry* / Q000502:physiology
chemical_list: C495273:CTNNA1 protein, human; D051178:alpha Catenin
keywords: cell adhesion; mechanotransduction; molecular dynamics; vinculin; α-catenin