1:00 PM-2:00 PM
The QBI Seminar Series is presenting Willow Coyote-Maestas. Willow is currently an HHMI Gilliam and NSF Graduate Fellow in Biochemistry, Molecular Biology, and Biophysics at University of Minnesota-Twin Cities. Willow received a Master of Science in Bioinformatics & Computational Biology at the University of Minnesota and a Bachelors in Science in Chemistry at The Evergreen State College.
Hosted by: James Fraser
Talk Title: Studying the diversification of ion channel regulation with insertional profiling
Abstract: Potassium (K ) channels underlie electrophysiology to enable brain and heart function. Channel architectures diversify through creating new regulatory mechanisms that couple cell signaling and K conductance. Within the K inward rectifier (Kir) channel family, the same architecture evolved to sense ATP, sodium, and cell signaling proteins. Allostery is the poorly understood distant coupling between regulatory and functional sites. We developed high throughput pipelines for measuring the intrinsic allosteric potential at every position of a protein. Based on the premise that sites with allosteric potential are more sensitive to perturbation than non-allosteric sites, Our idea is to measure the differential impact of inserting a protein domain on channel structure and function. Since previous methods yielded libraries unsuitable for this project, we developed a new DNA recombination library generation method. This method is broadly useful for studying and engineering mammalian membrane proteins.
Applying these methods to the Kir2.1 channel revealed that sites used in homologs for regulation had high allosteric potential. Indeed, inserting a light-switchable domain at these positions allows control of Kir2.1, supporting our hypothesis that these sites have allosteric potential. To find the physical basis for our observations, we conducted molecular dynamics simulations and found correlated motions between these regions and those involved in channel gating. Overall, this implies that Kir2.1 harbors latent allosteric potential used in homologs for regulation. Broadly, this could be an evolutionary mechanism by which protein regulation could evolve by harnessing intrinsic architectural coupling enabling proteins to fill cell signaling niches.
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