The Keating Lab studies protein-protein interactions important for eukaryotic signaling and human health. We apply an integrated program of modeling and experiment to probe the mechanisms of molecular interaction specificity and to develop molecules that selectively disrupt target interactions that can be used for research and therapy. We seek to understand how protein sequence controls interaction specificity and to develop new high-throughput assays that can provide data about the sequence-function relationship as well as models that can be used for interaction prediction and for protein or peptide design. Current work in the lab is focused on Bcl-2 family proteins that regulate apoptosis. The group has developed several different types of models to describe how the sequences of short BH3-motif helices determine their binding specificities for anti-apoptotic proteins in this family. Some models are based on protein structure and some are based on large experimental data sets and are derived using machine learning. The models are tested on extensive experimental data generated by the lab, and applied to design new molecules. This approach has led to tight-binding and selective peptide reagents that are useful for profiling the apoptotic status of cancer cells. The group also uses traditional biophysical and structural methods to understand in detail the mechanism of binding. New projects are expanding work in the group to protein domains such as TRAF and EVH1 domains that bind to short linear peptide motifs.
