Single-molecule studies of classical and desmosomal cadherin adhesion

Abstract

Classical cadherin and desmosomal cadherin cell-cell adhesion proteins play essential roles in tissue morphogenesis and in maintaining tissue integrity. Deficiencies in cadherin adhesion are hallmarks of diseases like cancers, skin diseases and cardiomyopathies. Structural studies and single molecule biophysical measurements have revealed critical similarities and surprising differences between these key adhesion proteins. This review summarizes our current understanding of the biophysics of classical and desmosomal cadherin adhesion and the molecular basis for their cross-talk. We focus on recent single molecule measurements, highlight key insights into the adhesion of cadherin extracellular regions and their relation to associated diseases, and identify major open questions in this exciting area of research.

Figure 1:. Classical and desmosomal cadherin adhesive complexes.

Cadherin ectodomains from opposing cells adhere to each other while intracellular regions interact with the cytoskeleton through effector proteins. (A) Classical cadherins form homodimers and associate with filamentous actin (F-actin) via β-catenin, α-catenin p120 catenin, and vinculin. (B) In contrast, desmosomal cadherins (Dsc and Dsg) typically form heterodimers and associate with intermediate filaments via plakoglobin, plakophilins and desmoplakin.

Figure 2:. Structure and biomechanics of E-cadherin trans dimers.

(A) E-cadherin monomers from opposing cells (red and blue) bind in a strand-swap dimer conformation. (B) Strand-swap dimers are formed by the exchange of conserved W2 residues between opposing EC1 domains (PDB: 3Q2V). Bound Ca²⁺ are denoted by gray spheres. (C) X-dimer interface consists of noncovalent surface interactions (hydrogen bonds and a salt bridge) between EC1 and EC2 domains near the Ca²⁺ binding site (PDB: 3LNH). (D) E-cadherins interconvert convert between an X-dimer (left) and strand-swap dimer (right) via an intermediate state (middle; simulated structure and interconversion pathway from reference [18]). (E) X-dimers form catch bonds. Catch bonds initially strengthen before weakening beyond a critical pulling force. (F) Strand-swap dimers form slip bonds. The lifetime of slip bonds decrease rapidly with force. (G-H) E-cadherin X-dimer before (G) and after (H) application of force. Tensile force flexes the interacting ectodomains such that hydrogen-bond donor and acceptor amino acids (cyan residues on blue monomer and orange residues on red monomer) are brought into registry. Panels (G, H) are adapted from reference [17]. Panel (F) is adapted from reference [18].

Figure 3:. Model for desmosome assembly.

Dsg2 (PDB code: 5ERD) and Ecad (PDB code: 3Q2V) initially interact to form a low-lifetime Ecad:Dsg2 complex. This requires prior formation of Ecad trans-homodimers. The Ecad:Dsg2 complex is then incorporated in the nascent desmosome that contains the weak Dsc2:Dsc2 homodimer (Dsc2 was constructed from PDB codes: 5ERP and 5J5J). Ecad:Dsg2 and Dsc2:Dsc2 complexes dissociate as the desmosome matures and a robust adhesive complex of trans Dsg2:Dsc2 heterodimers is formed. Figure was generated by positioning Ecad, Dsg2 and Dsc2 ectodomain structures in PyMOL based on model proposed in reference [41]. Lipid bilayer coordinates were obtained from reference [51]. Note: Only cadherin ectodomains are displayed in the figure.