The expertise of protein kinases lies in their dynamic structure, wherein they are able to modulate cellular signaling by their phosphotransferase activity. Only a few hundreds of protein kinases regulate key processes in human cells, and protein kinases play a pivotal role in health and disease. The present study dwells on understanding the working of the protein kinase-molecular switch as an allosteric network of "communities" composed of congruently dynamic residues that make up the protein kinase core. Girvan-Newman algorithm-based community maps of the kinase domain of cAMPdependent protein kinase A allow for a molecular explanation for the role of protein conformational entropy in its catalytic cycle. The community map of a mutant, Y204A, is analyzed vis-À-vis the wildtype protein to study the perturbations in its dynamic profile such that it interferes with transfer of the γ-phosphate to a protein substrate. Conventional biochemical measurements are used to ascertain the effect of these dynamic perturbations on the kinetic profiles of both proteins. These studies pave the way for understanding how mutations far from the kinase active site can alter its dynamic properties and catalytic function even when major structural perturbations are not obvious from static crystal structures.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Feb 7 2017|
Bibliographical noteFunding Information:
This work was supported by Public Health Service/NIH Grant GM100310 (to G.V. and S.S.T.) and NIH Grant GM034921 (to S.S.T.). Anton computer time was provided by the National Center for Multiscale Modeling of Biological System through Grant P41GM103712-S1 from the NIH and the Pittsburgh Supercomputing Center (PSC). The Anton machine at PSC was generously made available by D. E. Shaw Research.
Copyright 2017 Elsevier B.V., All rights reserved.
- Catalytic cycle
- Community maps
- Protein dynamics
- Protein kinases