Navigating the sequence space of Bcl-2-binding peptides

Navigating the sequence space of Bcl-2-binding peptides

Navigating the sequence space of Bcl-2-binding peptides (#69)

Amy Keating ¹

MIT, Cambridge, MA, United States

Protein-protein interactions among Bcl-2 family proteins regulate apoptosis. Anti-apoptotic members of the family, including Bcl-2, Bcl-x_L, Bcl-w, Mcl-1, and Bfl-1, sequester pro-apoptotic family members by binding tightly to an amphipathic alpha helix within them, blocking pro-death functions. Through this mechanism, overexpression of the anti-apoptotic proteins is implicated in oncogenesis and resistance to chemotherapy. Tight-binding and selective inhibitors of Bcl-2 family proteins can be used to diagnose the Bcl-2 dependencies of cancer cells and may be developed as therapeutics. The challenge of designing peptides that function as high-affinity and selective inhibitors of specific Bcl-2 family proteins poses a fundamental, challenging problem in protein engineering and a good opportunity to study principles of protein-peptide recognition. I will describe features of Bcl-2 family protein interactions and discuss approaches we have developed that integrate computational structure-based modeling with high-throughput screening to generate peptide-based inhibitors.

Authors contributing to this presentation.

Keating, A

Amy E. Keating is Professor of Biology and Biological Engineering at MIT and a member of the Koch Institute for Integrative Cancer Research. She joined the MIT faculty in 2002. As an undergraduate, she studied physics at Harvard, and she obtained her PhD in organic chemistry from UCLA, where she studied carbene reactions with Ken Houk and Miguel Garcia-Garibay. Prof. Keating was introduced to protein biochemistry as a postdoctoral fellow with Peter Kim of the Whitehead Institute and Bruce Tidor of MIT, and she has been working to understand how protein sequences and structures encode interaction specificity ever since. Her lab uses computational and experimental methods to measure protein interactions in high throughput, to develop models that predict binding, and to design new proteins and peptides with novel interaction properties. She teaches in the graduate curriculum and is Director of the MIT graduate program in Biology. She is President-Elect of the Protein Society, which she will lead from July 2019 – June 2021. Her trainees have gone on to careers in academia and at pharmaceutical and biotech companies. She is the busy mother of two teens and enjoys family travel, particularly road trips in the American west.

Navigating the sequence space of Bcl-2-binding peptides (#69)

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Keating, A

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