This talk describes a collaborative, multiscale investigation of fundamental protein interactions that drive the assembly of cadherin-mediated cell-cell adhesions. Cadherins are the molecular Velcro that zip all tissues together, by binding to cadherins on opposing membranes. Cadherins assemble into dense, organized arrays at intercellular junctions. The mechanisms driving this assembly are therefore critical to the organization and function of tissues. Here we used a combination of single molecule tracking, kinetic Monte Carlo simulations, and ensemble average measurements of cell binding kinetics to investigate protein interactions in this process. This integrated approach reveals that the assembly of cadherin adhesions involves strong cooperativity between adhesive (trans) interactions between proteins on opposing membranes and weak, lateral (cis) interactions between proteins on the same membrane. Crystal structures of cadherin extracellular domains suggest that the proteins could interact laterally, as well as bind opposing cadherins. However, the postulated cis interactions are undetectable in solution binding studies. Simulations and single molecule tracking revealed that 2D confinement on membrane surfaces enhances the lateral interactions between cadherins that in turn support protein clustering. We further show that the presence of cis interactions results in a 30fold enhancement in the lifetimes of trans (adhesive) bonds. This strong cis-trans cooperativity generates distinct features in measured cell binding kinetics, which are captured by kinetic Monte Carlo simulations of cadherin-mediated cell adhesion. These findings provide insights into the long-standing controversy of how weak cis and trans protein interactions act in concert to create strong macroscopic cell adhesions.

Molecular mechanisms in the assembly of intercellular adhesions

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.