title: Nanomechanics of the cadherin ectodomain: "canalization" by Ca2+ binding results in a new mechanical element.
abstract: Cadherins form a large family of calcium-dependent cell-cell adhesion receptors involved in development, morphogenesis, synaptogenesis, differentiation, and carcinogenesis through signal mechanotransduction using an adaptor complex that connects them to the cytoskeleton. However, the molecular mechanisms underlying mechanotransduction through cadherins remain unknown, although their extracellular region (ectodomain) is thought to be critical in this process. By single molecule force spectroscopy, molecular dynamics simulations, and protein engineering, here we have directly examined the nanomechanics of the C-cadherin ectodomain and found it to be strongly dependent on the calcium concentration. In the presence of calcium, the ectodomain extends through a defined ("canalized") pathway that involves two mechanical resistance elements: a mechanical clamp from the cadherin domains and a novel mechanostable component from the interdomain calcium-binding regions ("calcium rivet") that is abolished by magnesium replacement and in a mutant intended to impede calcium coordination. By contrast, in the absence of calcium, the mechanical response of the ectodomain becomes largely "decanalized" and destabilized. The cadherin ectodomain may therefore behave as a calcium-switched "mechanical antenna" with very different mechanical responses depending on calcium concentration (which would affect its mechanical integrity and force transmission capability). The versatile mechanical design of the cadherin ectodomain and its dependence on extracellular calcium facilitate a variety of mechanical responses that, we hypothesize, could influence the various adhesive properties mediated by cadherins in tissue morphogenesis, synaptic plasticity, and disease. Our work represents the first step toward the mechanical characterization of the cadherin system, opening the door to understanding the mechanical bases of its mechanotransduction.
authors.affiliation: Instituto Cajal/Consejo Superior de Investigaciones Científicas, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and Instituto Madrileño de Estudios Avanzados Nanociencia, Avenida Doctor Arce 37, E-28002 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Oroz
authors.forename: Alejandro
authors.initials: A
authors.lastname: Valbuena
authors.forename: Andrés Manuel
authors.initials: AM
authors.lastname: Vera
authors.forename: Jesús
authors.initials: J
authors.lastname: Mendieta
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.forename: Mariano
authors.initials: M
authors.lastname: Carrión-Vázquez
mesh_terms: D015820:Cadherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D011994:Recombinant Proteins; D002118:Calcium