P-cadherin and desmoglein-2 interact as strand-swap dimers and facilitate desmosome assembly

Abstract Desmosomes are essential adhesive junctions that mediate the integrity of tension prone tissue like the heart and skin. The classical cadherin, P-cadherin (Pcad), is known to play an important role in forming desmosomes. However, the molecular mechanisms by which Pcads enable desmosome assembly are unknown. Here, we combine single molecule Atomic Force Microscopy, super-resolution and confocal imaging, mutagenesis assays, and atomistic simulations to resolve the structural mechanisms by which Pcads facilitate the formation of desmosomes. We show that Pcads interact with the desmosomal cadherin Desmoglien-2 (Dsg2) on opposing cells, by mutually swapping β-strands terminated by conserved Tryptophan residues. A key determinant of this trans heterophilic strand-swap dimerization is the flexibility of a hinge on the swapped β -strands: stiffening this hinge reduces the likelihood of heterophilic strand-swap dimer formation. We demonstrate that while desmosome formation is impaired in cells that either lack classical cadherins or that express strand-swap deficient Pcad, introduction of strand-swap competent Pcad into these cells rescues desmosome assembly. We show that the heterophilic dimers formed by Pcad and Dsg2 interact in a robust and persistent manner, which retains Pcad within the desmosome throughout the maturation process. Significance Desmosomes are essential intercellular junctions that mediate the integrity of tissue like the heart and skin. Desmosomal defects are associated with numerous skin disorders, heart diseases, and cancer. The adhesive protein P-cadherin is known to play an important role in forming desmosomes. However, the molecular mechanisms by which P-cadherins enable desmosome assembly are unknown. Here, we show that desmosome formation is facilitated by the direct interaction of P-cadherin with the transmembrane desmosomal adhesion protein Desmoglein-2. We demonstrate that P-cadherin and Desmoglien-2 interact robustly by swapping flexible portions of their protein backbone and that this molecular complex nucleates desmosome formation. Our results resolve the biophysical basis by which different adhesive proteins interact and mediate stable desmosome assembly.