Role of actin filaments and cis binding in cadherin clustering and patterning

Cadherins build up clusters to maintain intercellular contact through trans and cis (lateral) bindings. Meanwhile, interactions between cadherin and the actin cytoskeleton through cadherin/F-actin linkers can affect cadherin dynamics by corralling and tethering cadherin molecules locally. Despite many experimental studies, a quantitative, mechanistic understanding of how cadherin and actin cytoskeleton interactions regulate cadherin clustering does not exist. To address this gap in knowledge, we developed a coarse-grained computational model of cadherin dynamics and their interaction with the actin cortex underlying the cell membrane. Our simulation predictions suggest that weak cis binding affinity between cadherin molecules can facilitate large cluster formation. We also found that cadherin movement inhibition by actin corralling is dependent on the concentration and length of actin filaments. This results in changes in cadherin clustering behaviors, as reflected by differences in cluster size and distribution as well as cadherin monomer trajectory. Strong cadherin/actin binding can enhance trans and cis interactions as well as cadherin clustering. By contrast, with weak cadherin/actin binding affinity, a competition between cadherin-actin binding and cis binding for a limited cadherin pool leads to temporary and unstable cadherin clusters.