Membrane Mediated Cooperativity Facilitates Cadherin Clustering in Model Membranes

Abstract

Cadherins are major cell-cell adhesion molecules in vertebrate tissue. They play a vital role in the development and maintenance of multicellular organisms. Cadherins show homophilic as well as heterophilic binding to members of their subfamily with a relatively low 3D binding affinity. In order to establish stable adhesion a combination of trans and cis interactions has been postulated to promote oligomerization and junction formation.In this project, we studied the dynamics of junction formation in a simplified model system consisting of a giant unilamellar vesicles adhering to a solid supported lipid bilayer via homophilic E cadherin - E cadherin bonds. We used reflection interference contrast microscopy to quantitatively extract vesicle membrane features (height and fluctuation amplitude) as well as to visualize the adhesion dynamics. Subtle differences in the initial membrane separation and fluctuation amplitude resulted in a variety of adhesion processes and steady states. We observed classical radial growth originating from one nucleation center leading to a dense array of bonds and strong adhesion. Other vesicles exhibited multiple nucleation centers or even gas-like behavior characterized by numerous bonds forming at the same time. The latter resulted in weak adhesion only and sometimes even unbinding.By developing a theoretical framework supported by Monte Carlo simulations, we are able to explain the extreme sensitivity of the experimentally observed growth processes. We suggest that the self-assembly of model adhesion junctions can be understood as an interplay between the effective 2D binding affinity, the characteristic nucleation time as well as the strength of membrane transmitted correlations. In vivo the observed sensitivity of the cadherin system can be exploited to regulate adhesion locally via biomembrane protrusions.