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© 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Meharena HS, Fan X, Ahuja LG, Keshwani MM, McClendon CL, Chen AM, et al. (2016) Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases. PLoS Biol 14(11): e2000127. doi:10.1371/journal.pbio.2000127

Abstract

Eukaryotic protein kinases regulate most cellular functions by phosphorylating targeted protein substrates through a highly conserved catalytic core. In the active state, the catalytic core oscillates between open, intermediate, and closed conformations. Currently, the intramolecular interactions that regulate the active state mechanics are not well understood. Here, using cAMP-dependent protein kinase as a representative model coupled with biochemical, biophysical, and computational techniques, we define a set of highly conserved electrostatic and hydrophobic interactions working harmoniously to regulate these mechanics. These include the previously identified salt bridge between a lysine from the [Beta]3-strand and a glutamate from the [alpha] C-helix as well as an electrostatic interaction between the phosphorylated activation loop and [alpha] C-helix and an ensemble of hydrophobic residues of the Regulatory spine and Shell. Moreover, for over three decades it was thought that the highly conserved [Beta]3-lysine was essential for phosphoryl transfer, but our findings show that the [Beta]3-lysine is not required for phosphoryl transfer but is essential for the active state mechanics.

Details

Title
Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases
Author
Meharena, Hiruy S; Fan, Xiaorui; Ahuja, Lalima G; Keshwani, Malik M; McClendon, Christopher L; Chen, Angela M; Adams, Joseph A; Taylor, Susan S
Section
Research Article
Publication year
2016
Publication date
Nov 2016
Publisher
Public Library of Science
ISSN
15449173
e-ISSN
15457885
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1849654575
Copyright
© 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Meharena HS, Fan X, Ahuja LG, Keshwani MM, McClendon CL, Chen AM, et al. (2016) Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases. PLoS Biol 14(11): e2000127. doi:10.1371/journal.pbio.2000127