I plan to discuss our most recent work in computational protein design (we have designed new, modular small-molecule sensors that function in living cells, and new protein shapes with atom-level control). I will then focus on a more biological problem: How do protein switches control diverse protein functions in the cell, given the interconnectedness of biological processes? We have focused on a paradigm molecular switch, the small GTPase Ran (or Gsp1 in our model system S. cerevisiae). Using systematic mutational perturbations of the switch, quantitative genetic interaction mapping, analysis of rewiring of physical interaction networks, in vitro biochemistry, and NMR, I will propose a model of how different biological processes are sensitive to different quantitative regimes of switch function. Our results highlight a considerable role of allostery in regulating the switch.
Speaker: Janja Kortemme, UC San Francisco
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