The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module

Kannan, N., Haste, N., Taylor, S. S., Neuwald, A. F. (January 2007) The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module. Proc Natl Acad Sci U S A, 104 (4). pp. 1272-7.

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URL: https://www.ncbi.nlm.nih.gov/pubmed/17227859
DOI: 10.1073/pnas.0610251104

Abstract

The catalytic activities of eukaryotic protein kinases (EPKs) are regulated by movement of the C-helix, movement of the N and C lobes upon ATP binding, and movement of the activation loop upon phosphorylation. Statistical analysis of the selective constraints associated with AGC kinase functional divergence reveals conserved interactions between these regulatory regions and three regions of the C-terminal tail (C-tail): the N-lobe tether (NLT), the active-site tether (AST), and the C-lobe tether (CLT). The NLT serves as a docking site for an upstream kinase PDK1 and, upon activation, positions the C-helix within the ATP binding pocket. The AST directly interacts with the ATP binding pocket, and the CLT interacts with the interlobe linker and the alphaC-beta4 loop, which appears to serve as a hinge for C-helix movement. The C-tail is a hallmark of AGC functional divergence inasmuch as most of the conserved core residues that distinguish AGC kinases from other EPKs are associated with the NLT, AST, or CLT. Moreover, several AGC catalytic core conserved residues that interact with the C-tail strikingly diverge from the canonical residues observed at corresponding positions in nearly all other EPKs, suggesting that the catalytic core may have coevolved with the C-tail in AGC kinases. These observations, along with the fact that the C-tail is needed for catalytic activity suggests that the C-tail is a cis-acting regulatory module that can also serve as a regulatory "handle," to which trans-acting cellular components can bind to modulate activity.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Sequence Animals Binding Sites Humans Models, Molecular Molecular Sequence Data Protein Kinases/chemistry/metabolism/*physiology Sequence Homology, Amino Acid Substrate Specificity
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > AGC kinase
bioinformatics > genomics and proteomics > design > protein design
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
CSHL Authors:
Communities: CSHL labs > Neuwald lab
Depositing User: CSHL Librarian
Date: 23 January 2007
Date Deposited: 11 Nov 2011 16:29
Last Modified: 09 Nov 2017 16:07
PMCID: PMC1783090
Related URLs:
URI: http://repository.cshl.edu/id/eprint/23057

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