University of Minnesota
School of Physics & Astronomy

Physics and Astronomy Calendar

Thursday, April 26th 2018
10:10 am:
Biophysics Seminar in 120 PAN
Speaker: Gianluigi Veglia, Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota
Subject: Role of conformational dynamics on protein kinases function and dysfunction

Eukaryotic protein kinases (EPKs) are phosphoryl transferase that mediate several signaling events and constitute major pharmaceutical targets. cAMP-dependent protein kinase A is a prototypical kinase of paramount biological importance as it is involved in a myriad of cellular processes. Using nuclear magnetic resonance (NMR) spectroscopy, we probed the enzyme’s intramolecular allosteric network along the catalytic cycle. We discovered that kinase A conformational motions are highly organized and correlated during turnover. Fast dynamics in the ps-ns time scale are directly linked to the conformational entropy of binding, revealing the mechanisms for positive and negative allosteric cooperativity that drive both substrate binding and product release. Slow dynamics in the in the micro second to milli second time scale are responsible for the conformational transitions from catalytically incompetent to competent states. Disruption of these dynamics leads to dysfunctional signaling and disease. Since the C-subunit of protein kinase A is highly conserved within the kinase family, the present study offers unprecedented mechanistic insights into intramolecular signaling for designing novel kinase activators or inhibitors.

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