Molecular plasticity of -catenin: New insights from single-molecule measurements and MD simulation

The multifunctional protein, -catenin, has essential roles in cell adhesion and, through the Wnt signaling pathway, in controlling cell differentiation, development, and generation of cancer. Could distinct molecular forms of -catenin underlie these two functions? Our single-molecule force spectroscopy of armadillo -catenin, with molecular dynamics (MD) simulation, suggests a model in which the cell generates various forms of -catenin, in equilibrium. We find -catenin and the transcriptional factor Tcf4 form two complexes with different affinities. Specific cellular response is achieved by the ligand binding to a particular matching preexisting conformer. Our MD simulation indicates that complexes derive from two conformers of the core region of the protein, whose preexisting molecular forms could arise from small variations in flexible regions of the -catenin main binding site. This mechanism for the generation of the various forms offers a route to tailoring future therapeutic strategies.