Principal Investigator Amy Keating
The Bcl-2 family comprises ~25 proteins important for controlling apoptosis. Critical junctures that govern cellular life-vs-death decisions are regulated by specific interactions among pro- and anti-apoptotic members of this family. The delicate balance between these is often disrupted in cancers. Five mammalian anti-apoptotic family members have a conserved helical, globular structure, and all known family members share a weakly conserved short BH3 (Bcl-2 homology 3) sequence. Peptides corresponding to the BH3 region have been shown in several instances to adopt an Éø-helical structure and to bind into a hydrophobic groove on the surface of anti-apoptotic proteins. We are interested in how the interaction specificity of Bcl-2 family proteins is determined by sequence and structure and are exploring this using x-ray crystallography, mutational analysis and computational protein design. Using new computational methods for varying the backbone structure of Éø-helices, we have designed several novel ligands for the anti-apoptotic protein Bcl-xL. Solution binding studies confirm that many of these designed peptides bind with low- to mid- nanomolar affinity and have specificity profiles that differ from those of known native BH3s.