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Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases.


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 ?3-strand and a glutamate from the ?C-helix as well as an electrostatic interaction between the phosphorylated activation loop and ?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 ?3-lysine was essential for phosphoryl transfer, but our findings show that the ?3-lysine is not required for phosphoryl transfer but is essential for the active state mechanics.

SUBMITTER: Meharena HS 

PROVIDER: S-EPMC5130182 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases.

Meharena Hiruy S HS   Fan Xiaorui X   Ahuja Lalima G LG   Keshwani Malik M MM   McClendon Christopher L CL   Chen Angela M AM   Adams Joseph A JA   Taylor Susan S SS  

PLoS biology 20161130 11


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,  ...[more]

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