Structural basis of molecular recognition among classical cadherins mediating cell adhesion

Cadherins are type-I membrane glycoproteins that primarily participate in calcium dependent cell adhesion and homotypic cell sorting in various stages of embryonic development. Besides their crucial role in cellular and physiological processes, increasing studies highlight their involvement in pathophysiological functions ranging from cancer progression and metastasis to being entry receptors for pathogens. Cadherins mediate these cellular processes through homophilic, as well as heterophilic interactions (within and outside the superfamily) by their membrane distal ectodomains. This review provides an in-depth structural perspective of molecular recognition among type-I and type-II classical cadherins. Furthermore, this review offers structural insights into different dimeric assemblies like the 'strand-swap dimer' and 'X-dimer' as well as mechanisms relating these dimer forms like 'two-step adhesion' and 'encounter complex'. Alongside providing structural details, this review connects structural studies to bond mechanics merging crystallographic and single-molecule force spectroscopic findings. Finally, the review discusses the recent discoveries on dimeric intermediates that uncover prospects of further research beyond two-step adhesion.