Molecular mechanism of E-Cadherin mediated mechano-sensing

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E-cadherin provides the mechanical inter-cellular link at adherens junctions. It serves as a dynamic hub that translates cell-cell adhesion forces into biochemical downstream processes, the molecular mechanisms of which remain to be explored. The intrinsically disordered cytoplasmic tail of E-cadherin binds to p120, -catenin, and indirectly to -catenin and actin. Mechanical force leads to a displacement of p120 and -catenin from the E-cadherin tail, processes which are critical for tension-regulated cell division. The proposed work aims at unravelling the mechanisms underlying these E-cadherin mechano-sensing functions, using atomistic simulations and bioinformatics analyses. We hypothesize that the E-cadherin tail uncoils and straightens under the tensile force of adherens junctions, and thereby reorients the attached elongated armadillo-repeat catenin molecules along the force direction, which in turn directly affects the E-cadherin/catenin interactions. We will test this hypothesis by constructing atomistically resolved models of the E-cadherin transmembrane and cytosolic domains embedded into the membrane, and successively adding the catenin binding partners to the disordered E-cadherin tail. We will then subject these structures to Molecular Dynamics simulations in presence and absence of tensile forces, mimicking the adherens junction conditions. Given the comparably short E-cadherin cytosolic tail and the rotational constraint the mechanical force has on the bound catenins and their binding interfaces, we expect the force-dependent dynamics obtained from simulations to show substantial changes in the cadherin/catenin interactions. Such changes could manifest themselves as an altered p120-membrane interaction, steric hindrance among the two adjacently bound p120 and -catenin molecules, or a decrease of interfacial interactions at the E-cadherin/catenin binding sites. We will additionally also address the effect of E-cadherin phosphorylation on these processes by additional simulations with modified phosphorylation states. Finally, we will ask whether the observed mechano-sensing mechanisms are similarly at play among the large families of conventional cadherins and catenins, by large-scale sequence alignments and coevolution analysis.Our work programme will provide unprecedented insights into the force response of cadherin/catenin complexes and will give mechanistic explanations for their mechano-sensing role. The outcomes of our simulations will be directly tested by mutagenesis experiments in collaboration, and will also help to interpret and guide experiments on the more complex cellular and tissue levels undertaken within the SPP.