Advertisement

Tuning the Kinetics of Cadherin Adhesion

  • Sanjeevi Sivasankar
    Correspondence
    Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA
    Affiliations
    Department of Physics and Astronomy, Iowa State University, Ames, Iowa, USA

    Ames Laboratory, United States Department of Energy, Ames, Iowa, USA
    Search for articles by this author
      Cadherins are Ca2+-dependent cell–cell adhesion proteins that maintain the structural integrity of the epidermis; their principle function is to resist mechanical force. This review summarizes the biophysical mechanisms by which classical cadherins tune adhesion and withstand mechanical stress. We first relate the structure of classical cadherins to their equilibrium binding properties. We then review the role of mechanical perturbations in tuning the kinetics of cadherin adhesion. In particular, we highlight recent studies that show that cadherins form three types of adhesive bonds: catch bonds, which become longer lived and lock in the presence of tensile force; slip bonds, which become shorter lived when pulled; and ideal bonds, which are insensitive to tugging.

      Abbreviations

      EC
      extracellular
      WT
      wild-type

      Introduction

      The epidermis serves as a physical barrier that protects organisms from their external environment. This multilayered tissue is composed of keratinocytes bound together by two types of cell–cell adhesion complexes: desmosomes and adherens junctions (
      • Jensen P.J.
      • Wheelock M.J.
      The relationships among adhesion, stratification and differentiation in keratinocytes.
      ). The primary adhesive components of both these structures are the cadherin family of Ca2+-dependent transmembrane proteins (
      • Gumbiner B.M.
      Regulation of cadherin-mediated adhesion in morphogenesis.
      ;
      • Halbleib J.M.
      • Nelson W.J.
      Cadherins in development: cell adhesion, sorting, and tissue morphogenesis.
      ;
      • Green K.J.
      • Simpson C.L.
      Desmosomes: new perspectives on a classic.
      ;
      • Al-Amoudi A.
      • Frangakis A.S.
      Structural studies on desmosomes.
      ;
      • Niessen C.M.
      • Leckband D.
      • Yap A.S.
      Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation.
      ). Desmosomes are composed of two types of desmosomal cadherins (desmocollin and desmoglein) (
      • Green K.J.
      • Simpson C.L.
      Desmosomes: new perspectives on a classic.
      ;
      • Desai B.V.
      • Harmon R.M.
      • Green K.J.
      Desmosomes at a glance.
      ), whereas epidermal adherens junctions contain a single classical type-1 cadherin (either E-cadherin or P-cadherin) (
      • Jensen P.J.
      • Wheelock M.J.
      The relationships among adhesion, stratification and differentiation in keratinocytes.
      ;
      • Halbleib J.M.
      • Nelson W.J.
      Cadherins in development: cell adhesion, sorting, and tissue morphogenesis.
      ). Both desmosomes and adherens junctions act in a coordinated manner to help the epidermis withstand mechanical stress. Although the interactions that mediate desmosomal cadherin binding are not completely understood, the structural basis of classical cadherin adhesion has been extensively characterized.
      Classical cadherins share a conserved cytoplasmic domain, and an ectodomain containing five tandem extracellular (EC) repeats. Their expression levels vary within the epidermis; although E-cadherins are present in all keratinocytes, expression of P-cadherins is limited to the basal layer (
      • Takeichi M.
      The cadherins: cell-cell adhesion molecules controlling animal morphogenesis.
      ;
      • Halbleib J.M.
      • Nelson W.J.
      Cadherins in development: cell adhesion, sorting, and tissue morphogenesis.
      ). Adhesion is mediated by the cadherin ectodomain, whereas the cytoplasmic region binds to adaptor proteins that link cadherins indirectly to the cytoskeleton, regulate cadherin turnover, and modulate actin assembly (
      • Nelson W.J.
      • Nusse R.
      Convergence of Wnt, beta-catenin, and cadherin pathways.
      ;
      • Takeichi M.
      The cadherin superfamily in neuronal connections and interactions.
      ;
      • Niessen C.M.
      • Leckband D.
      • Yap A.S.
      Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation.
      ). As the epidermis is a self-renewing tissue with a continuous upward movement of cells, cadherins dynamically tune their adhesive strength in order to preserve epidermal barrier integrity (
      • Niessen C.M.
      Tight junctions/adherens junctions: basic structure and function.
      ). Epidermal cadherin–knockout studies in mice show that loss of E-cadherin correlates with a loss of adherens junctions, altered epidermal differentiation, and loss of hair follicles (
      • Young P.
      • Boussadia O.
      • Halfter H.
      • et al.
      E-cadherin controls adherens junctions in the epidermis and the renewal of hair follicles.
      ;
      • Tinkle C.L.
      • Lechler T.
      • Pasolli H.A.
      • et al.
      Conditional targeting of E-cadherin in skin: Insights into hyperproliferative and degenerative responses.
      ). Similarly, deletion of α-catenin, an adaptor protein associated with the cadherin cytoplasmic domain, results in impaired adhesion and epidermal detachment (
      • Vasioukhin V.
      • Bauer C.
      • Degenstein L.
      • et al.
      Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin.
      ).
      Cell–cell adhesion is a dynamic process, and classical cadherins tailor their binding kinetics in order to withstand mechanical perturbations. While the equilibrium binding properties of classical cadherins have been extensively characterized (
      • Brasch J.
      • Harrison O.J.
      • Honig B.
      • et al.
      Thinking outside the cell: how cadherins drive adhesion.
      ), the role of mechanical force in altering cadherin binding is only now being measured. Recent studies show that upon being exposed to mechanical perturbation, E-cadherins change their unbinding kinetics (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). These kinetic changes are not manifested in solution or in the absence of mechanical loading, but are critical for cadherin adhesion.
      This brief review summarizes our current understanding of the effect of mechanical force on the kinetics of E-cadherin adhesion. We focus on the ectodomain; the role of the cytoplasmic domain and its associated proteins has been reviewed elsewhere (
      • Schwartz M.A.
      • DeSimone D.W.
      Cell adhesion receptors in mechanotransduction.
      ;
      • Papusheva E.
      • Heisenberg C.-P.
      Spatial organization of adhesion: force-dependent regulation and function in tissue morphogenesis.
      ;
      • Gomez G.A.
      • McLachlan R.W.
      • Yap A.S.
      Productive tension: force-sensing and homeostasis of cell-cell junctions.
      ;
      • Leckband D.E.
      • le Duc Q.
      • Wang N.
      • et al.
      Mechanotransduction at cadherin-mediated adhesions.
      ;
      • Ladoux B.
      • Nicolas A.
      Physically based principles of cell adhesion mechanosensitivity in tissues.
      ). We begin by relating the structure of E-cadherins to their equilibrium binding properties. We then review the role of mechanical perturbations in tuning the kinetics of adhesion. Finally, we discuss major open questions and future directions in this exciting area of research.

      Adhesive States of Classical Cadherins

      Classical cadherins adhere via “trans” interactions where ectodomains from opposing cells bridge the inter-membrane gap and interact with each other. Adhesion is strengthened by the cooperative self-assembly of cadherins on the same cell into cis clusters (
      • Brasch J.
      • Harrison O.J.
      • Honig B.
      • et al.
      Thinking outside the cell: how cadherins drive adhesion.
      ).

      Structure and kinetics of trans-adhesive states

      Structural studies of both the complete ectodomain of type-I classical C-cadherin (EC1–5) (
      • Boggon T.J.
      • Murray J.
      • Chappuis-Flament S.
      • et al.
      C-cadherin ectodomain structure and implications for cell adhesion mechanisms.
      ) and of smaller fragments of E-Cadherin and N-Cadherin (
      • Shapiro L.
      • Fannon A.M.
      • Kwong P.D.
      • et al.
      Structural basis of cell-cell adhesion by cadherins.
      ;
      • Nagar B.
      • Overduin M.
      • Ikura M.
      • et al.
      Structural basis of calcium-induced E-cadherin rigidification and dimerization.
      ;
      • Pertz O.
      • Bozic D.
      • Koch A.W.
      • et al.
      A new crystal structure, Ca2+ dependence and mutational analysis reveal molecular details of E-cadherin homoassociation.
      ;
      • Haussinger D.
      • Ahrens T.
      • Aberle T.
      • et al.
      Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography.
      ;
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ) have identified key interactions that mediate trans adhesion (Figure 1). The primary adhesive conformation involves the interaction of opposing EC1 domains and is termed the strand-swapped dimer (Figure 1a). In this structure, N-terminal β-strands between opposing EC1 domains are swapped, and the side chain of a conserved tryptophan at position 2 (W2) is inserted into a pocket on their adhesive partner (
      • Shapiro L.
      • Fannon A.M.
      • Kwong P.D.
      • et al.
      Structural basis of cell-cell adhesion by cadherins.
      ;
      • Boggon T.J.
      • Murray J.
      • Chappuis-Flament S.
      • et al.
      C-cadherin ectodomain structure and implications for cell adhesion mechanisms.
      ;
      • Haussinger D.
      • Ahrens T.
      • Aberle T.
      • et al.
      Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography.
      ;
      • Parisini E.
      • Higgins J.M.G.
      • Liu J.H.
      • et al.
      The crystal structure of human E-cadherin domains 1 and 2, and comparison with other cadherins in the context of adhesion mechanism.
      ) (Figure 1a). The physiological relevance of this adhesive interface has been confirmed in numerous mutational, structural, and cellular studies (
      • Tamura K.
      • Shan W.S.
      • Hendrickson W.A.
      • et al.
      Structure-function analysis of cell adhesion by neural (N-) cadherin.
      ;
      • Pertz O.
      • Bozic D.
      • Koch A.W.
      • et al.
      A new crystal structure, Ca2+ dependence and mutational analysis reveal molecular details of E-cadherin homoassociation.
      ;
      • Troyanovsky R.B.
      • Sokolov E.
      • Troyanovsky S.M.
      Adhesive and lateral E-cadherin dimers are mediated by the same interface.
      ;
      • Shan W.
      • Yagita Y.
      • Wang Z.
      • et al.
      The minimal essential unit for cadherin-mediated intercellular adhesion comprises extracellular domains 1 and 2.
      ;
      • Harrison O.J.
      • Corps E.M.
      • Berge T.
      • et al.
      The mechanism of cell adhesion by classical cadherins: the role of domain 1.
      ;
      • Prakasam A.
      • Chien Y.H.
      • Maruthamuthu V.
      • et al.
      Calcium site mutations in cadherin: impact on adhesion and evidence of cooperativity.
      ). In solution, the affinity for strand-swap dimer formation is low; dissociation constants (Kd) for trans dimers of the full-length ectodomain of C-cadherin measured using analytical ultra centrifugation is 64μM (
      • Chappuis-Flament S.
      • Wong E.
      • Hicks L.D.
      • et al.
      Multiple cadherin extracellular repeats mediate homophilic binding and adhesion.
      ). Similarly, EC1–2 domains of E-cadherin expressed in mammalian and bacterial cells have trans-dimer Kd values of 97μM (
      • Katsamba P.
      • Carroll K.
      • Ahlsen G.
      • et al.
      Linking molecular affinity and cellular specificity in cadherin-mediated adhesion.
      ) and 80μM (
      • Koch A.W.
      • Pokutta S.
      • Lustig A.
      • et al.
      Calcium binding and homoassociation of E-cadherin domains.
      ), respectively.
      Figure thumbnail gr1
      Figure 1Adhesive states of classical cadherin and the pathway for cadherin binding. (a) The extracellular region of type-I classical cadherin is composed of five tandem extracellular (EC) domains. Linkers between successive EC domains are each bound to three Ca2+ ions, which give the ectodomain its characteristic curvature. Ectodomains from opposing cells (shown in green and magenta) adhere across the inter-membrane gap via “trans” interactions. The primary trans interface involves the interaction of opposing EC1 domains and is termed the strand-swapped dimer. In this conformation, N-terminal β-strands between opposing EC1 domains are swapped, and the side chain of a conserved tryptophan at position 2 (W2) is inserted into a pocket on their adhesive partner. (b) Before strand swapping, cadherin ectodomains form a non-swapped, intermediate conformation called an X-dimer. This conformation is formed by extensive surface interactions between the base of the EC1 domain, EC1–2 inter-domain linker region, and the apex of domain EC2. (c) Cadherin monomers adopt a “closed” conformation where W2 is docked into each monomer’s binding pocket. Monomers from opposing cells interact to form X-dimers and then proceed to swap W2 residues to form a strand-swap dimer. The Kd of the EC1–2 domains of W2A E-cadherin X-dimers is 916μM (
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ), whereas the Kd of the EC1–2 domains of wild-type E-cadherin strand-swap dimers is 97μM (
      • Katsamba P.
      • Carroll K.
      • Ahlsen G.
      • et al.
      Linking molecular affinity and cellular specificity in cadherin-mediated adhesion.
      ).
      Before strand swapping, cadherin monomers are in a “closed” conformation where W2 is docked into each monomer’s binding pocket; the monomers thus act as competitive inhibitors of strand swapping (
      • Chen C.P.
      • Posy S.
      • Ben-Shaul A.
      • et al.
      Specificity of cell-cell adhesion by classical cadherins: critical role for low-affinity dimerization through beta-strand swapping.
      ). The closed monomeric conformation places a strain on the short swapping strand owing to its anchorage at one end by the W2 and at the other by a Ca2+ ion; relieving this conformational strain is the driving force for strand swapping (
      • Vendome J.
      • Posy S.
      • Jin X.
      • et al.
      Molecular design principles underlying Beta-strand swapping in the adhesive dimerization of cadherins.
      ). Equilibrium affinity measurements using analytical ultra centrifugation show that mutations that relieve strain in the swapping strand in E-cadherin monomers decrease dimerization affinities (
      • Vendome J.
      • Posy S.
      • Jin X.
      • et al.
      Molecular design principles underlying Beta-strand swapping in the adhesive dimerization of cadherins.
      ). Single-molecule fluorescence resonance energy transfer experiments suggest that before swapping N-terminal β-strands, E-cadherin monomers first form a non-swapped, intermediate “encounter complex” (Figure 1c) (
      • Sivasankar S.
      • Zhang Y.
      • Nelson W.J.
      • et al.
      Characterizing the initial encounter complex in cadherin adhesion.
      ). E-cadherins can be trapped in this encounter complex by mutating W2 (
      • Sivasankar S.
      • Zhang Y.
      • Nelson W.J.
      • et al.
      Characterizing the initial encounter complex in cadherin adhesion.
      ); consequently, W2A fragments weakly adhere to each other (
      • Prakasam A.
      • Chien Y.H.
      • Maruthamuthu V.
      • et al.
      Calcium site mutations in cadherin: impact on adhesion and evidence of cooperativity.
      ;
      • Sivasankar S.
      • Zhang Y.
      • Nelson W.J.
      • et al.
      Characterizing the initial encounter complex in cadherin adhesion.
      ). Recently, the atomic resolution structure of the encounter complex has been resolved in W2A mutants (Figure 1b). This conformation, called an X-dimer, is formed by extensive surface interactions between the base of the EC1 domain, EC1–2 interdomain linker region, and the apex of domain EC2 (
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ) (Figure 1b). The affinity for X-dimer formation in solution is significantly weaker than strand-swap dimers; the Kd of W2A cadherin X-dimers is an order of magnitude higher (916μM) than wild-type (WT) cadherin strand-swap dimers (
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ).
      Mutations in the cadherin X-dimer–binding interface alter the kinetics of strand swapping but do not change the structure of the strand-swap dimer. When a key Lys 14 residue in the X-dimer-binding interface is mutated to a Glu, the trans dimers are virtually indistinguishable from WT cadherin strand-swap dimers (
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ). As measured using surface plasmon resonance, the K14E mutants show no binding in a short time frame, suggesting that their binding rate (on-rate) is low. Similarly, sedimentation velocity analytical ultra centrifugation and size-exclusion chromatography show that the monomer to strand-swap dimer conversion is impeded in these mutants (
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ). Presumably, lower on-rates are measured, as the formation of X-dimers, which serve as kinetic intermediates during strand swapping (Figure 1c), are impaired in the K14E mutants. In epithelial cells, inactivation of X-dimers result in extraordinarily stable cell–cell junctions; this has been interpreted to indicate that X-dimers are an intermediate in the pathway to dissociation of strand-swap dimers (
      • Hong S.J.
      • Troyanovsky R.B.
      • Troyanovsky S.M.
      Cadherin exits the junction by switching its adhesive bond.
      ). Analytical ultra centrifugation measurements show that the Kd of the K14E mutants are virtually indistinguishable from WT cadherin, which suggests that besides their low on-rate, the dissociation (off-rate) of these mutants is also decreased (
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ). However, in contrast to these studies, recent single-molecule force measurements indicate that the dissociation rate of K14E is similar to WT cadherin (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). Consequently, the molecular role of X-dimers in the dissociation of strand-swap dimers is unclear.

      Structure and kinetics of cis-adhesive states

      Cadherin adhesion is enhanced by their lateral assembly on the cell surface (
      • Takeda H.
      • Shimoyama Y.
      • Nagafuchi A.
      • et al.
      E-cadherin functions as a cis-dimer at the cell-cell adhesive interface in vivo.
      ;
      • Kim Y.J.
      • Johnson K.R.
      • Wheelock M.J.
      N-cadherin-mediated cell motility requires cis dimers.
      ). However, the biophysical mechanisms by which cis clustering boosts adhesion are just beginning to be understood. Early studies showed that beads decorated with cadherin pairs aggregated to a greater extent than beads with immobilized monomers (
      • Brieher W.M.
      • Yap A.S.
      • Gumbiner B.M.
      Lateral dimerization is required for the homophilic binding activity of C-cadherin.
      ). Although these data were interpreted to suggest that cadherin ectodomains form cis dimers, recent single-molecule experiments show that ectodomains located adjacent to each other cooperatively enhance the probability of adhesion even if they do not associate with each other in a cis geometry (
      • Zhang Y.
      • Sivasankar S.
      • Nelson W.J.
      • et al.
      Resolving cadherin interactions and binding cooperativity at the single molecule level.
      ).
      On the basis of contacts observed in X-ray crystal structures of a range of classical cadherins, it has been proposed that interactions between the apex of EC1 and the base of EC2 of neighboring cadherins mediate dimerization in a cis orientation (
      • Boggon T.J.
      • Murray J.
      • Chappuis-Flament S.
      • et al.
      C-cadherin ectodomain structure and implications for cell adhesion mechanisms.
      ;
      • Harrison O.J.
      • Jin X.S.
      • Hong S.J.
      • et al.
      The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins.
      ). These interactions are, however, not observed in nuclear magnetic resonance measurements of EC1–2 (
      • Haussinger D.
      • Ahrens T.
      • Sass H.J.
      • et al.
      Calcium-dependent homoassociation of E-cadherin by NMR spectroscopy: changes in mobility, conformation and mapping of contact regions.
      ), indicating that their Kd exceeds 1mM (
      • Harrison O.J.
      • Jin X.S.
      • Hong S.J.
      • et al.
      The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins.
      ). Similarly, single-molecule fluorescence resonance energy transfer experiments could not detect cis-dimer formation between two cadherin ectodomains that were located adjacent to each other in a configuration that would permit lateral dimerization (
      • Zhang Y.
      • Sivasankar S.
      • Nelson W.J.
      • et al.
      Resolving cadherin interactions and binding cooperativity at the single molecule level.
      ). This discrepancy is explained by recent theoretical studies, which predict that the cis assembly of cadherin ectodomains requires prior trans dimerization (
      • Wu Y.H.
      • Jin X.S.
      • Harrison O.
      • et al.
      Cooperativity between trans and cis interactions in cadherin-mediated junction formation.
      ,
      • Wu Y.
      • Vendome J.
      • Shapiro L.
      • et al.
      Transforming binding affinities from three dimensions to two with application to cadherin clustering.
      ). When trans dimers are formed, the conformational flexibility of ectodomains is markedly reduced, which lowers the entropic penalty associated with cis-dimer formation (
      • Wu Y.
      • Vendome J.
      • Shapiro L.
      • et al.
      Transforming binding affinities from three dimensions to two with application to cadherin clustering.
      ).
      In qualitative agreement with these predictions, micropipette manipulation experiments show that the binding of cadherins from opposing cells occurs in two stages: an initial rapid stage ascribed to trans adhesion, followed by a second slower stage interpreted to occur owing to cis clustering (
      • Chien Y.H.
      • Jiang N.
      • Li F.
      • et al.
      Two stage cadherin kinetics require multiple extracellular domains but not the cytoplasmic region.
      ). However, although the first stage requires the EC1 domain as expected for trans-dimer formation, EC3 is required for the second adhesive state (
      • Chien Y.H.
      • Jiang N.
      • Li F.
      • et al.
      Two stage cadherin kinetics require multiple extracellular domains but not the cytoplasmic region.
      ). Micropipette experiments also demonstrate that hypoglycosylation of EC2 and EC3 enhance the lateral assembly of ectodomains (
      • Langer M.D.
      • Guo H.B.
      • Shashikanth N.
      • et al.
      N-glycosylation alters cadherin-mediated intercellular binding kinetics.
      ).

      Mechanical Tension Alters the Kinetics of Cadherin Adhesion

      The structural and biophysical studies described above provide a detailed picture of the kinetic determinants of classical cadherin binding in equilibrium, under force-free conditions. However, the molecular mechanisms by which cadherins alter their binding kinetics in response to mechanical forces are still unclear.
      When cadherin trans dimers are pulled apart, they can form one of three distinct types of bonds (
      • Dembo M.
      • Torney D.C.
      • Saxman K.
      • et al.
      The reaction-limited kinetics of membrane-to-surface adhesion and detachment.
      ;
      • Dembo M.
      On peeling an adherent cell from a surface.
      ): (i) Slip bonds, which weaken and have a higher off-rate when pulled; (ii) Catch bonds, which counter-intuitively strengthen such that their off-rates decrease; and (iii) Ideal bonds, which are unaffected by mechanical stress. Slip bonds are the most commonly observed interactions in biology. Catch bonds provide a way for the interacting proteins to grip tightly in the presence of tugging forces. Finally, although ideal bonds were theoretically proposed more than a decade ago (
      • Dembo M.
      • Torney D.C.
      • Saxman K.
      • et al.
      The reaction-limited kinetics of membrane-to-surface adhesion and detachment.
      ;
      • Dembo M.
      On peeling an adherent cell from a surface.
      ), they had not been experimentally observed in any biological system.
      Recently, single-molecule atomic force microscope force measurements were used to show that E-cadherins form bonds with catch, slip, and ideal mechanical properties (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). The lifetimes of E-cadherin-binding conformations were measured as they were subjected to different pulling forces. These experiments showed that although W2A mutant X-dimers formed catch bonds, WT and K14E strand-swap dimers formed slip bonds (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ) (Figure 2a and b). WT cadherins were also shown to form ideal bonds, which were hypothesized to arise as X-dimers converted to a strand-swap conformation (Figure 2b) (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ).
      Figure thumbnail gr2
      Figure 2Mechanical force tunes the kinetics of cadherin adhesion.
      Adapted from
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      . (a) X-dimers form catch bonds, which become longer lived and lock in the presence of tensile force. When W2A cadherin X-dimers are pulled, their bond lifetimes increase with force. After reaching a maximum at a critical force of ∼30pN, the lifetimes decrease. (b) Strand-swap dimers form slip bonds, which become shorter lived when pulled. Slip bonds are formed by K14E mutants that interact for short and long periods of time and also by wild-type (WT) cadherins that interact for long periods of time. However, when WT cadherins interact for a short period of time, they form ideal bonds that are insensitive to force. (c) Hypothetical mechanism by which keratinocytes resist tensile forces during skin renewal and wound healing. As skin cells reposition themselves, E-cadherins bind rapidly to form X-dimers that allow cells to grip strongly under load. In immobile keratinocytes, E-cadherins form more robust strand-swap dimers that have a high affinity in the absence of force.

      X-dimers form catch bonds

      When X-dimers were tugged, their bond lifetimes increased with force, indicative of a catch bond. After reaching a maximum at a critical force of∼30pN, the lifetimes decreased with force (Figure 2a). A similar behavior was measured when WT cadherins were forced into an X-dimer conformation by competitively inhibiting strand swapping using free W in solution (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). X-dimer catch bonds are observed because the cadherins reorient when they are pulled such that they form transient, force-induced bonds and lock more tightly.
      Although this was the first observation of catch bonds in cadherin adhesion, these bonds have previously been measured with other adhesive proteins such as selectins (
      • Marshall B.T.
      • Long M.
      • Piper J.W.
      • et al.
      Direct observation of catch bonds involving cell-adhesion molecules.
      ;
      • Sarangapani K.K.
      • Yago T.
      • Klopocki A.G.
      • et al.
      Low force decelerates L-selectin dissociation from P-selectin glycoprotein ligand-1 and endoglycan.
      ;
      • Yago T.
      • Wu J.H.
      • Wey C.D.
      • et al.
      Catch bonds govern adhesion through L-selectin at threshold shear.
      ), FimH (
      • Thomas W.E.
      • Trintchina E.
      • Forero M.
      • et al.
      Bacterial adhesion to target cells enhanced by shear force.
      ;
      • Le Trong I.
      • Aprikian P.
      • Kidd B.A.
      • et al.
      Structural basis for mechanical force regulation of the adhesin FimH via finger trap-like beta sheet twisting.
      ), and integrins (
      • Kong F.
      • Garcia A.J.
      • Mould A.P.
      • et al.
      Demonstration of catch bonds between an integrin and its ligand.
      ). Although it is tempting to speculate that the physiological role of X-dimer catch bonds is to allow cells to grip tightly and lock in place when pulled, this hypothesis remains to be tested.

      Catch bonds resolve discrepancies between solution and surface force measurements

      Over a decade ago, surface force apparatus measurements of the interactions between cadherin ectodomains immobilized on lipid membranes suggested that classical cadherins bind in three distinct conformations (
      • Sivasankar S.
      • Gumbiner B.
      • Leckband D.
      Direct measurements of multiple adhesive alignments and unbinding trajectories between cadherin extracellular domains.
      ). The weakest conformation required W2, and corresponded to a strand-swapped dimer (
      • Zhu B.
      • Chappuis-Flament S.
      • Wong E.
      • et al.
      Functional analysis of the structural basis of homophilic cadherin adhesion.
      ;
      • Prakasam A.K.
      • Maruthamuthu V.
      • Leckband D.E.
      Similarities between heterophilic and homophilic cadherin adhesion.
      ). The second conformation had an intermediate binding strength and required EC1-2 (
      • Zhu B.
      • Chappuis-Flament S.
      • Wong E.
      • et al.
      Functional analysis of the structural basis of homophilic cadherin adhesion.
      ); based on recent structural data, it is likely that this adhesive state corresponds to the X-dimer complex. The third and strongest adhesion required the EC3 domains to interact directly (
      • Zhu B.
      • Chappuis-Flament S.
      • Wong E.
      • et al.
      Functional analysis of the structural basis of homophilic cadherin adhesion.
      ); although this adhesive state likely corresponds to a cis-dimer structure, this remains to be confirmed. Single-molecule atomic force microscope force measurements of the interaction of different classical cadherins confirmed the results of the ensemble surface force apparatus measurements (
      • Perret E.
      • Leung A.
      • Feracci H.
      • et al.
      Trans-bonded pairs of E-cadherin exhibit a remarkable hierarchy of mechanical strengths.
      ;
      • Bayas M.V.
      • Leung A.
      • Evans E.
      • et al.
      Lifetime measurements reveal kinetic differences between homophilic cadherin bonds.
      ;
      • Shi Q.M.
      • Chien Y.H.
      • Leckband D.
      Biophysical properties of cadherin bonds do not predict cell sorting.
      ,
      • Shi Q.M.
      • Maruthamuthu V.
      • Li F.
      • et al.
      Allosteric cross talk between cadherin extracellular domains.
      ).
      It was initially believed that the surface force apparatus measurement of stronger adhesion between X-dimers compared with strand-swap dimers directly contradicted the results of solution affinity measurements, which showed that X-dimers have higher off-rates than strand-swap dimers. However, the discovery of X-dimer catch bonds resolves this apparent discrepancy (Figure 2a). As catch bonds strengthen in the presence of force, X-dimer adhesion, which is weak in the absence of force, becomes stronger when pulled.

      Strand-swap dimers form slip bonds

      As strand-swap dimers have a higher binding affinity than X-dimers (
      • Katsamba P.
      • Carroll K.
      • Ahlsen G.
      • et al.
      Linking molecular affinity and cellular specificity in cadherin-mediated adhesion.
      ;
      • Harrison O.J.
      • Bahna F.
      • Katsamba P.S.
      • et al.
      Two-step adhesive binding by classical cadherins.
      ), WT cadherins form strand-swap dimers when they interact for long periods of time. Single-molecule atomic force microscope force-clamp experiments showed that these WT cadherin strand-swap dimers formed slip bonds; their bond lifetimes decreased with increasing tensile force (Figure 2b). Not surprisingly, identical slip bonds were formed by the K14E strand-swap dimers (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ) (Figure 2b). The intrinsic off-rate of both the WT E-cadherin and K14E strand-swap dimers was 1.6s−1 (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ), which is similar to an off-rate of 0.7s−1 measured for WT E-cadherins using nuclear magnetic resonance (
      • Haussinger D.
      • Ahrens T.
      • Aberle T.
      • et al.
      Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography.
      ).

      Ideal bonds are formed as X-dimers transition to a strand-swap conformation

      Besides forming catch and slip bonds, cadherins also form ideal bonds that behave like mechanical dampers and prevent the abrupt jolting of cells. When WT cadherin interaction time was decreased, the lifetimes of their interactions were independent of force; they formed ideal bonds (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ) (Figure 2b). It was hypothesized that ideal bonds correspond to an intermediate state that is formed when X-dimers transition to strand-swap binding (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). However, the structure of the intermediate state and the molecular contacts responsible for ideal bond formation still need to be resolved.

      Future Directions

      Catch, slip, and ideal bonds suggest a physical mechanism that E-cadherins use to resist tensile force as cells rearrange during skin renewal and wound healing. It is tempting to speculate that as keratinocytes reposition themselves, E-cadherins bind rapidly to form X-dimer catch bonds that allow cells to grip strongly under load (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ) (Figure 2c). Over time, the X-dimers proceed to form more robust strand-swap dimers that have a high affinity in the absence of force (Figure 2c); this conversion is facilitated by an intermediate conformation that is insensitive to tensile force (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). However, it is currently unclear whether keratinocytes use such a mechanism to tune adhesive properties. Studying cadherin bond mechanics in living cells will be a crucial first step to addressing this question.
      Besides mediating robust adhesion, classical cadherins have a key role in mechanotransduction by sensing physical stimuli at cell–cell junctions, transmitting them to the cytoplasm, and activating a biochemical response (
      • Ladoux B.
      • Anon E.
      • Lambert M.
      • et al.
      Strength dependence of cadherin-mediated adhesions.
      ;
      • le Duc Q.
      • Shi Q.
      • Blonk I.
      • et al.
      Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner.
      ;
      • Liu Z.J.
      • Tan J.L.
      • Cohen D.M.
      • et al.
      Mechanical tugging force regulates the size of cell-cell junctions.
      ;
      • Weber G.F.
      • Bjerke M.A.
      • DeSimone D.W.
      A mechanoresponsive cadherin-keratin complex directs polarized protrusive behavior and collective cell migration.
      ). It is believed that cadherins along with their adaptor proteins, β-catenin and α-catenin, form the core force-bearing unit in the transmission of mechanical signals (
      • Leckband D.E.
      • le Duc Q.
      • Wang N.
      • et al.
      Mechanotransduction at cadherin-mediated adhesions.
      ). To accomplish this, it is critical that the interactions between cadherins and catenins remain intact when exposed to force. However, the force-dependent binding kinetics of these interactions have not yet been studied. Furthermore, the role of these adaptor proteins in altering cadherin mechanical properties is still an open question. For instance, it is known that the adaptor protein α-catenin has an important role in strengthening cadherin bonds following initial adhesion (
      • Bajpai S.
      • Correia J.
      • Feng Y.F.
      • et al.
      Alpha-catenin mediates initial E-cadherin-dependent cell-cell recognition and subsequent bond strengthening.
      ). Whether α-catenin and other adaptor proteins alter the force-dependent kinetics of cadherin bonds needs to be investigated.
      Some of the discrepancies in cadherin binding measured using solution affinity measurements and force measurements arise owing to differences between cadherin interactions in solution, under force-independent conditions, and cadherin adhesion in the presence of mechanical stress. The discovery that cadherins vary their lifetimes in response to force reconciles some of these differences (
      • Rakshit S.
      • Zhang Y.
      • Manibog K.
      • et al.
      Ideal, catch, and slip bonds in cadherin adhesion.
      ). However, several open questions remain. For instance, the molecular interactions by which cadherins form catch bonds are not known. Furthermore, the hypothesis that ideal bonds correspond to an intermediate state, which is formed as cadherin X-dimers transition to a strand-swap conformation, needs to be tested at the molecular level. Finally, the role that X-dimers have in the dissociation of strand-swap dimers is unclear.

      ACKNOWLEDGMENTS

      I thank Dr Sabyasachi Rakshit for his help in preparing Figure 2. This work was supported in part by a Basil O’Connor Starter Scholar Award from the March of Dimes Foundation and a grant from the American Heart Association.

      REFERENCES

        • Al-Amoudi A.
        • Frangakis A.S.
        Structural studies on desmosomes.
        Biochem Soc Trans. 2008; 36: 181-187
        • Bajpai S.
        • Correia J.
        • Feng Y.F.
        • et al.
        Alpha-catenin mediates initial E-cadherin-dependent cell-cell recognition and subsequent bond strengthening.
        Proc Natl Acad Sci USA. 2008; 105: 18331-18336
        • Bayas M.V.
        • Leung A.
        • Evans E.
        • et al.
        Lifetime measurements reveal kinetic differences between homophilic cadherin bonds.
        Biophys J. 2006; 90: 1385-1395
        • Boggon T.J.
        • Murray J.
        • Chappuis-Flament S.
        • et al.
        C-cadherin ectodomain structure and implications for cell adhesion mechanisms.
        Science. 2002; 296: 1308-1313
        • Brasch J.
        • Harrison O.J.
        • Honig B.
        • et al.
        Thinking outside the cell: how cadherins drive adhesion.
        Trends Cell Biol. 2012; 22: 299-310
        • Brieher W.M.
        • Yap A.S.
        • Gumbiner B.M.
        Lateral dimerization is required for the homophilic binding activity of C-cadherin.
        J Cell Biol. 1996; 135: 487-496
        • Chappuis-Flament S.
        • Wong E.
        • Hicks L.D.
        • et al.
        Multiple cadherin extracellular repeats mediate homophilic binding and adhesion.
        J Cell Biol. 2001; 154: 231-243
        • Chen C.P.
        • Posy S.
        • Ben-Shaul A.
        • et al.
        Specificity of cell-cell adhesion by classical cadherins: critical role for low-affinity dimerization through beta-strand swapping.
        Proc Natl Acad Sci USA. 2005; 102: 8531-8536
        • Chien Y.H.
        • Jiang N.
        • Li F.
        • et al.
        Two stage cadherin kinetics require multiple extracellular domains but not the cytoplasmic region.
        J Biol Chem. 2008; 283: 1848-1856
        • Dembo M.
        On peeling an adherent cell from a surface.
        in: Lectures on Mathematics in the Life Sciences, Some Mathematical Problems in Biology. Vol. 24. American Mathematical Society, Providence, RI, USA1994: 51-77
        • Dembo M.
        • Torney D.C.
        • Saxman K.
        • et al.
        The reaction-limited kinetics of membrane-to-surface adhesion and detachment.
        Proc R Soc Lond B Biol Sci. 1988; 234: 55-83
        • Desai B.V.
        • Harmon R.M.
        • Green K.J.
        Desmosomes at a glance.
        J Cell Sci. 2009; 122: 4401-4407
        • Gomez G.A.
        • McLachlan R.W.
        • Yap A.S.
        Productive tension: force-sensing and homeostasis of cell-cell junctions.
        Trends Cell Biol. 2011; 21: 499-505
        • Green K.J.
        • Simpson C.L.
        Desmosomes: new perspectives on a classic.
        J Invest Dermatol. 2007; 127: 2499-2515
        • Gumbiner B.M.
        Regulation of cadherin-mediated adhesion in morphogenesis.
        Nat Rev Mol Cell Biol. 2005; 6: 622-634
        • Halbleib J.M.
        • Nelson W.J.
        Cadherins in development: cell adhesion, sorting, and tissue morphogenesis.
        Genes Dev. 2006; 20: 3199-3214
        • Harrison O.J.
        • Bahna F.
        • Katsamba P.S.
        • et al.
        Two-step adhesive binding by classical cadherins.
        Nat Struct Mol Biol. 2010; 17: 348-357
        • Harrison O.J.
        • Corps E.M.
        • Berge T.
        • et al.
        The mechanism of cell adhesion by classical cadherins: the role of domain 1.
        J Cell Sci. 2005; 118: 711-721
        • Harrison O.J.
        • Jin X.S.
        • Hong S.J.
        • et al.
        The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins.
        Structure. 2011; 19: 244-256
        • Haussinger D.
        • Ahrens T.
        • Aberle T.
        • et al.
        Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography.
        EMBO J. 2004; 23: 1699-1708
        • Haussinger D.
        • Ahrens T.
        • Sass H.J.
        • et al.
        Calcium-dependent homoassociation of E-cadherin by NMR spectroscopy: changes in mobility, conformation and mapping of contact regions.
        J Mol Biol. 2002; 324: 823-839
        • Hong S.J.
        • Troyanovsky R.B.
        • Troyanovsky S.M.
        Cadherin exits the junction by switching its adhesive bond.
        J Cell Biol. 2011; 192: 1073-1083
        • Jensen P.J.
        • Wheelock M.J.
        The relationships among adhesion, stratification and differentiation in keratinocytes.
        Cell Death Differ. 1996; 3: 357-371
        • Katsamba P.
        • Carroll K.
        • Ahlsen G.
        • et al.
        Linking molecular affinity and cellular specificity in cadherin-mediated adhesion.
        Proc Natl Acad Sci USA. 2009; 106: 11594-11599
        • Kim Y.J.
        • Johnson K.R.
        • Wheelock M.J.
        N-cadherin-mediated cell motility requires cis dimers.
        Cell Commun Adhes. 2005; 12: 23-39
        • Koch A.W.
        • Pokutta S.
        • Lustig A.
        • et al.
        Calcium binding and homoassociation of E-cadherin domains.
        Biochemistry. 1997; 36: 7697-7705
        • Kong F.
        • Garcia A.J.
        • Mould A.P.
        • et al.
        Demonstration of catch bonds between an integrin and its ligand.
        J Cell Biol. 2009; 185: 1275-1284
        • Ladoux B.
        • Anon E.
        • Lambert M.
        • et al.
        Strength dependence of cadherin-mediated adhesions.
        Biophys J. 2010; 98: 534-542
        • Ladoux B.
        • Nicolas A.
        Physically based principles of cell adhesion mechanosensitivity in tissues.
        Rep Prog Phys. 2012; 75: 116601
        • Langer M.D.
        • Guo H.B.
        • Shashikanth N.
        • et al.
        N-glycosylation alters cadherin-mediated intercellular binding kinetics.
        J Cell Sci. 2012; 125: 2478-2485
        • le Duc Q.
        • Shi Q.
        • Blonk I.
        • et al.
        Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner.
        J Cell Biol. 2010; 189: 1107-1115
        • Le Trong I.
        • Aprikian P.
        • Kidd B.A.
        • et al.
        Structural basis for mechanical force regulation of the adhesin FimH via finger trap-like beta sheet twisting.
        Cell. 2010; 141: 645-655
        • Leckband D.E.
        • le Duc Q.
        • Wang N.
        • et al.
        Mechanotransduction at cadherin-mediated adhesions.
        Curr Opin Cell Biol. 2011; 23: 523-530
        • Liu Z.J.
        • Tan J.L.
        • Cohen D.M.
        • et al.
        Mechanical tugging force regulates the size of cell-cell junctions.
        Proc Natl Acad Sci USA. 2010; 107: 9944-9949
        • Marshall B.T.
        • Long M.
        • Piper J.W.
        • et al.
        Direct observation of catch bonds involving cell-adhesion molecules.
        Nature. 2003; 423: 190-193
        • Nagar B.
        • Overduin M.
        • Ikura M.
        • et al.
        Structural basis of calcium-induced E-cadherin rigidification and dimerization.
        Nature. 1996; 380: 360-364
        • Nelson W.J.
        • Nusse R.
        Convergence of Wnt, beta-catenin, and cadherin pathways.
        Science. 2004; 303: 1483-1487
        • Niessen C.M.
        Tight junctions/adherens junctions: basic structure and function.
        J Invest Dermatol. 2007; 127: 2525-2532
        • Niessen C.M.
        • Leckband D.
        • Yap A.S.
        Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation.
        Physiol Rev. 2011; 91: 691-731
        • Papusheva E.
        • Heisenberg C.-P.
        Spatial organization of adhesion: force-dependent regulation and function in tissue morphogenesis.
        EMBO J. 2010; 29: 2753-2768
        • Parisini E.
        • Higgins J.M.G.
        • Liu J.H.
        • et al.
        The crystal structure of human E-cadherin domains 1 and 2, and comparison with other cadherins in the context of adhesion mechanism.
        J Mol Biol. 2007; 373: 401-411
        • Perret E.
        • Leung A.
        • Feracci H.
        • et al.
        Trans-bonded pairs of E-cadherin exhibit a remarkable hierarchy of mechanical strengths.
        Proc Natl Acad Sci USA. 2004; 101: 16472-16477
        • Pertz O.
        • Bozic D.
        • Koch A.W.
        • et al.
        A new crystal structure, Ca2+ dependence and mutational analysis reveal molecular details of E-cadherin homoassociation.
        EMBO J. 1999; 18: 1738-1747
        • Prakasam A.
        • Chien Y.H.
        • Maruthamuthu V.
        • et al.
        Calcium site mutations in cadherin: impact on adhesion and evidence of cooperativity.
        Biochemistry. 2006; 45: 6930-6939
        • Prakasam A.K.
        • Maruthamuthu V.
        • Leckband D.E.
        Similarities between heterophilic and homophilic cadherin adhesion.
        Proc Natl Acad Sci USA. 2006; 103: 15434-15439
        • Rakshit S.
        • Zhang Y.
        • Manibog K.
        • et al.
        Ideal, catch, and slip bonds in cadherin adhesion.
        Proc Natl Acad Sci USA. 2012; 109: 18815-18820
        • Sarangapani K.K.
        • Yago T.
        • Klopocki A.G.
        • et al.
        Low force decelerates L-selectin dissociation from P-selectin glycoprotein ligand-1 and endoglycan.
        J Biol Chem. 2004; 279: 2291-2298
        • Schwartz M.A.
        • DeSimone D.W.
        Cell adhesion receptors in mechanotransduction.
        Curr Opin Cell Biol. 2008; 20: 551-556
        • Shan W.
        • Yagita Y.
        • Wang Z.
        • et al.
        The minimal essential unit for cadherin-mediated intercellular adhesion comprises extracellular domains 1 and 2.
        J Biol Chem. 2004; 279: 55914-55923
        • Shapiro L.
        • Fannon A.M.
        • Kwong P.D.
        • et al.
        Structural basis of cell-cell adhesion by cadherins.
        Nature. 1995; 374: 327-337
        • Shi Q.M.
        • Chien Y.H.
        • Leckband D.
        Biophysical properties of cadherin bonds do not predict cell sorting.
        J Biol Chem. 2008; 283: 28454-28463
        • Shi Q.M.
        • Maruthamuthu V.
        • Li F.
        • et al.
        Allosteric cross talk between cadherin extracellular domains.
        Biophys J. 2010; 99: 95-104
        • Sivasankar S.
        • Gumbiner B.
        • Leckband D.
        Direct measurements of multiple adhesive alignments and unbinding trajectories between cadherin extracellular domains.
        Biophys J. 2001; 80: 1758-1768
        • Sivasankar S.
        • Zhang Y.
        • Nelson W.J.
        • et al.
        Characterizing the initial encounter complex in cadherin adhesion.
        Structure. 2009; 17: 1075-1081
        • Takeda H.
        • Shimoyama Y.
        • Nagafuchi A.
        • et al.
        E-cadherin functions as a cis-dimer at the cell-cell adhesive interface in vivo.
        Nat Struct Biol. 1999; 6: 310-312
        • Takeichi M.
        The cadherins: cell-cell adhesion molecules controlling animal morphogenesis.
        Development. 1988; 102: 639-655
        • Takeichi M.
        The cadherin superfamily in neuronal connections and interactions.
        Nat Rev Neurosci. 2007; 8: 11-20
        • Tamura K.
        • Shan W.S.
        • Hendrickson W.A.
        • et al.
        Structure-function analysis of cell adhesion by neural (N-) cadherin.
        Neuron. 1998; 20: 1153-1163
        • Thomas W.E.
        • Trintchina E.
        • Forero M.
        • et al.
        Bacterial adhesion to target cells enhanced by shear force.
        Cell. 2002; 109: 913-923
        • Tinkle C.L.
        • Lechler T.
        • Pasolli H.A.
        • et al.
        Conditional targeting of E-cadherin in skin: Insights into hyperproliferative and degenerative responses.
        Proc Natl Acad Sci USA. 2004; 101: 552-557
        • Troyanovsky R.B.
        • Sokolov E.
        • Troyanovsky S.M.
        Adhesive and lateral E-cadherin dimers are mediated by the same interface.
        Mol Cell Biol. 2003; 23: 7965-7972
        • Vasioukhin V.
        • Bauer C.
        • Degenstein L.
        • et al.
        Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin.
        Cell. 2001; 104: 605-617
        • Vendome J.
        • Posy S.
        • Jin X.
        • et al.
        Molecular design principles underlying Beta-strand swapping in the adhesive dimerization of cadherins.
        Nat Struct Mol Biol. 2011; 18: 693-700
        • Weber G.F.
        • Bjerke M.A.
        • DeSimone D.W.
        A mechanoresponsive cadherin-keratin complex directs polarized protrusive behavior and collective cell migration.
        Dev Cell. 2012; 22: 104-115
        • Wu Y.
        • Vendome J.
        • Shapiro L.
        • et al.
        Transforming binding affinities from three dimensions to two with application to cadherin clustering.
        Nature. 2011; 475: 510-513
        • Wu Y.H.
        • Jin X.S.
        • Harrison O.
        • et al.
        Cooperativity between trans and cis interactions in cadherin-mediated junction formation.
        Proc Natl Acad Sci USA. 2010; 107: 17592-17597
        • Yago T.
        • Wu J.H.
        • Wey C.D.
        • et al.
        Catch bonds govern adhesion through L-selectin at threshold shear.
        J Cell Biol. 2004; 166: 913-923
        • Young P.
        • Boussadia O.
        • Halfter H.
        • et al.
        E-cadherin controls adherens junctions in the epidermis and the renewal of hair follicles.
        EMBO J. 2003; 22: 5723-5733
        • Zhang Y.
        • Sivasankar S.
        • Nelson W.J.
        • et al.
        Resolving cadherin interactions and binding cooperativity at the single molecule level.
        Proc Natl Acad Sci USA. 2009; 106: 109-114
        • Zhu B.
        • Chappuis-Flament S.
        • Wong E.
        • et al.
        Functional analysis of the structural basis of homophilic cadherin adhesion.
        Biophys J. 2003; 84: 4033-4042