KILU seminar: AI-Guided Protein Design to Control Cellular Signaling

The KILU seminar series provides an opportunity to learn about exciting current research. In addition, it is an opportuseries opportunity to meet, exchange ideas and discuss science with colleagues from all around KILU and beyond.

Speaker
Magnus Bauer, Baker Lab, Institute for Protein Design, University of Washington, USA

Topic
AI-Guided Protein Design to Control Cellular Signaling

Time and place
9 April, 15:15-16:00, lecture hall A at Kemicentrum

Coffee and cake will be served before the seminar, starting at 15:00, on a first-come, first-served basis (outside lecture hall A).

Abstract

I will present two lines of work using AI-guided protein design to engineer interfaces with cellular signaling. First, I will describe the de novo design of genetically encoded miniproteins that directly modulate kinase activity by binding regulatory surfaces on the kinase domain itself. Using focal adhesion kinase (FAK) as a model system, I designed binders to allosteric sites and identified modulators that either inhibit or activate kinase activity. Biochemical characterization of the most potent designs revealed low-nanomolar inhibitors as well as activators that increase FAK activity by more than two-fold. I will further show how this approach can be extended across kinase families by redesigning FAK binders to target Src, establishing a general strategy for selective and genetically encoded control of kinase signaling.

Second, I will present RoseTTAFold Diffusion 2 for Molecular Interfaces (RFD2-MI), an all-atom generative framework for designing binders to covalently modified proteins, including phosphorylated targets. Using this approach, we generated binders to five phosphotyrosine sites in CD3ε, EGFR, INSR, and STAT5 that bind their intended phosphorylated targets with affinities comparable to native phosphotyrosine-binding domains while discriminating against unphosphorylated and off-target peptides. In living cells, single-particle tracking experiments further show stimulus-dependent recruitment of an EGFR phosphosite binder to the membrane, demonstrating selective recognition of a signaling state in its cellular context.