Search for: All records

Crystal structures of many cell–cell adhesion receptors reveal the formation of linear “molecular zippers” comprising an ordered one-dimensional array of proteins that form both intercellular ( trans ) and intracellular ( cis ) interactions. The clustered protocadherins (cPcdhs) provide an exemplar of this phenomenon and use it as a basis of barcoding of vertebrate neurons. Here, we report both Metropolis and kinetic Monte Carlo simulations of cPcdh zipper formation using simplified models of cPcdhs that nevertheless capture essential features of their three-dimensional structure. The simulations reveal that the formation of long zippers is an implicit feature of cPcdh structure and is driven by their cis and trans interactions that have been quantitatively characterized in previous work. Moreover, in agreement with cryo-electron tomography studies, the zippers are found to organize into two-dimensional arrays even in the absence of attractive interactions between individual zippers. Our results suggest that the formation of ordered two-dimensional arrays of linear zippers of adhesion proteins is a common feature of cell–cell interfaces. From the perspective of simulations, they demonstrate the importance of a realistic depiction of adhesion protein structure and interactions if important biological phenomena are to be properly captured. 

The interaction between TNFα and TNFR1 is essential in maintaining tissue development and immune responses. While TNFR1 is a cell surface receptor, TNFα exists in both soluble and membrane-bound forms. Interestingly, it was found that the activation of TNFR1-mediated signaling pathways is preferentially through the soluble form of TNFα, which can also induce the clustering of TNFR1 on plasma membrane of living cells. We developed a multiscale simulation framework to compare receptor clustering induced by soluble and membrane-bound ligands. Comparing with the freely diffusive soluble ligands, we hypothesize that the conformational dynamics of membrane-bound ligands are restricted, which affects the clustering of ligand-receptor complexes at cell-cell interfaces. Our simulation revealed that only small clusters can form if TNFα is bound on cell surface. In contrast, the clustering triggered by soluble TNFα is more dynamic, and the size of clusters is statistically larger. We therefore demonstrated the impact of membrane-bound ligand on dynamics of receptor clustering. Moreover, considering that larger TNFα-TNFR1 clusters is more likely to provide spatial platform for downstream signaling pathway, our studies offer new mechanistic insights about why the activation of TNFR1-mediated signaling pathways is not preferred by membrane-bound form of TNFα.