1. Integration of signaling in the kinome: Architecture and regulation of the αC Helix.
- Author
-
Taylor SS, Shaw AS, Kannan N, and Kornev AP
- Subjects
- Adenosine Triphosphate chemistry, Amino Acid Motifs, Catalytic Domain, Eukaryota, Phosphorylation, Protein Kinases metabolism, Protein Kinases chemistry, Protein Structure, Secondary, Signal Transduction genetics, Structure-Activity Relationship
- Abstract
Eukaryotic protein kinases have evolved to be highly regulated and dynamic molecular switches that are typically kept in an inactive state and then activated in response to extracellular signals. The hallmark signature of an active kinase is a hydrophobic spine called the regulatory (R) spine, which consists of four residues, two in the N-lobe and two in the C-lobe. RS1 is in the catalytic loop, RS2 is the Phe in the DFG motif, RS3 is at the C-terminus of the αC-Helix, and RS4 is at the beginning of β4. Assembly of the R-spine is typically facilitated by phosphorylation of the Activation Loop. The assembled R-spine brings together all of the functional motifs that are essential for transferring the phosphate from ATP to a tethered protein substrate. This includes the G-Loop, which anchors the ATP, the catalytic loop, the DFG motif fused to the Activation Loop, and the αC-Helix. We focus here on the properties of the αC-Helix showing 1) how residues communicate with different parts of the molecule, 2) how it is recruited to the active site as a consequence of assembling of the R-spine, and 3) how it is regulated by linkers/motifs/proteins that lie outside the conserved kinase core. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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