title: Resolving the molecular mechanism of cadherin catch bond formation.
abstract: Classical cadherin Ca(2+)-dependent cell-cell adhesion proteins play key roles in embryogenesis and in maintaining tissue integrity. Cadherins mediate robust adhesion by binding in multiple conformations. One of these adhesive states, called an X-dimer, forms catch bonds that strengthen and become longer lived in the presence of mechanical force. Here we use single-molecule force-clamp spectroscopy with an atomic force microscope along with molecular dynamics and steered molecular dynamics simulations to resolve the molecular mechanisms underlying catch bond formation and the role of Ca(2+) ions in this process. Our data suggest that tensile force bends the cadherin extracellular region such that they form long-lived, force-induced hydrogen bonds that lock X-dimers into tighter contact. When Ca(2+) concentration is decreased, fewer de novo hydrogen bonds are formed and catch bond formation is eliminated.
authors.affiliation: 1] Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA [2] Ames Laboratory, United States Department of Energy, Ames, Iowa 50011, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Manibog
authors.affiliation: 1] Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA [2] Ames Laboratory, United States Department of Energy, Ames, Iowa 50011, USA [3].
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: 1] Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA [2] Ames Laboratory, United States Department of Energy, Ames, Iowa 50011, USA [3].
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Rakshit
authors.affiliation: 1] Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA [2] Ames Laboratory, United States Department of Energy, Ames, Iowa 50011, USA.
authors.forename: Sanjeevi
authors.initials: S
authors.lastname: Sivasankar
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D018625:Microscopy, Atomic Force; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D015820:Cadherins; D002118:Calcium