Structural and energetic basis of cadherin binding specificity
Lawrence Shapiro and Barry Honig
This project investigated the structural and energetic basis of cell-cell adhesion, which helps shape tissues and “wire” the neural networks of the brain. Initially focused on adhesion mediated by the cadherin family of proteins, the project expanded to include the binding of neurexin and neuroligin proteins that play a role in synapse formation. For the cadherins, our research showed how "strand-swapping" between molecules affects their mutual affinity, and demonstrated for the first time a connection between molecular binding affinity and adhesive strength between cells. Further modeling showed how the affinities of two cadherins, toward each other and toward themselves, define the patterns formed by cells that carry these surface molecules. We also demonstrated how the precise sequence of two proteins changes their affinity, and used that information to convert a normally nonbinding cadherin to a binding form. Overall, the synergy between theory and experiment allowed us to make important connections between molecular and cellular properties to clarify how the differing binding energies of molecules presented on the surfaces of cells determine their adhesion and the tissues they form.
Adhesion between cadherin family members, primarily through preferential interaction between similar molecules, provides a key driving force in the development of tissue architecture. The crucial specificity that helps sculpt tissue shape arises from subtle differences among family members. In the past, neither sequence analysis nor observations on known crystal structures had revealed the structural and energetic origins of cadherin specificity. It became clear that computational studies were needed, both to generate testable hypotheses and to interpret experimental results. We pursued a joint program encompassing energetic analysis of protein-protein interfaces, structure prediction, x-ray crystallography, biophysical measurements of binding, and cell-sorting experiments. This program has produced several important results: