Deciphering the Structural Basis of Eukaryotic Protein Kinase Regulation: e1001680

Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essen...

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Bibliographic Details
Published in:PLoS biology 2013-10, Vol.11 (10)
Main Authors: Meharena, Hiruy S, Chang, Philip, Keshwani, Malik M, Oruganty, Krishnadev, Nene, Aishwarya K, Kannan, Natarajan, Taylor, Susan S, Kornev, Alexandr P
Format: Article
Language:English
Subjects:
Diabetes
Experiments
Kinases
Phosphorylation
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Summary:Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors.
ISSN:1544-9173
1545-7885
DOI:10.1371/journal.pbio.1001680