Deciphering the structural basis of eukaryotic protein kinase regulation

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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Veröffentlicht in:PLoS biology 2013-10, Vol.11 (10), p.e1001680
Hauptverfasser: Meharena, Hiruy S, Chang, Philip, Keshwani, Malik M, Oruganty, Krishnadev, Nene, Aishwarya K, Kannan, Natarajan, Taylor, Susan S, Kornev, Alexandr P
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container_issue 10
container_start_page e1001680
container_title PLoS biology
container_volume 11
creator Meharena, Hiruy S
Chang, Philip
Keshwani, Malik M
Oruganty, Krishnadev
Nene, Aishwarya K
Kannan, Natarajan
Taylor, Susan S
Kornev, Alexandr P
description 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.
doi_str_mv 10.1371/journal.pbio.1001680
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subjects Amino Acid Motifs
Amino Acids - metabolism
Biocatalysis
Databases, Protein
Diabetes
Enzyme Activation
Eukaryota - enzymology
Experiments
Health aspects
Hydrophobic and Hydrophilic Interactions
Kinases
Models, Molecular
Phosphorylation
Physiological aspects
Protein binding
Protein kinases
Protein Kinases - chemistry
Protein Kinases - metabolism
Sequence Alignment
Structure-Activity Relationship
title Deciphering the structural basis of eukaryotic protein kinase regulation
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