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Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone
- Source :
- PLoS ONE, Vol 12, Iss 11, p e0186089 (2017), PLoS ONE
- Publication Year :
- 2017
- Publisher :
- Public Library of Science (PLoS), 2017.
-
Abstract
- The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK family are of particular interest as functional diversification among these kinases may be related to variations in chaperone dependencies and can be exploited in drug discovery of personalized therapeutic agents. In this work, we report the results of a computational investigation of several members of CDK family (CDK5, CDK6, CDK9) that represented a broad repertoire of chaperone dependencies-from nonclient CDK5, to weak client CDK6, and strong client CDK9. By using molecular simulations of multiple crystal structures we characterized conformational ensembles and collective dynamics of CDK proteins. We found that the elevated dynamics of CDK9 can trigger imbalances in cooperative collective motions and reduce stability of the active fold, thus creating a cascade of favorable conditions for chaperone intervention. The ensemble-based modeling of residue interaction networks and community analysis determined how differences in modularity of allosteric networks and topography of communication pathways can be linked with the client status of CDK proteins. This analysis unveiled depleted modularity of the allosteric network in CDK9 that alters distribution of communication pathways and leads to impaired signaling in the client kinase. According to our results, these network features may uniquely define chaperone dependencies of CDK clients. The perturbation response scanning and rigidity decomposition approaches identified regulatory hotspots that mediate differences in stability and cooperativity of allosteric interaction networks in the CDK structures. By combining these synergistic approaches, our study revealed dynamic and network signatures that can differentiate kinase clients and rationalize subtle divergences in the activation mechanisms of CDK family members. The therapeutic implications of these results are illustrated by identifying structural hotspots of pathogenic mutations that preferentially target regions of the increased flexibility to enable modulation of activation changes. Our study offers a network-based perspective on dynamic kinase mechanisms and drug design by unravelling relationships between protein kinase dynamics, allosteric communications and chaperone dependencies.
- Subjects :
- Proteomics
0301 basic medicine
Chaperonins
Protein Conformation
lcsh:Medicine
Cell Cycle Proteins
Biochemistry
0302 clinical medicine
Macromolecular Structure Analysis
Centrality
Enzyme Chemistry
lcsh:Science
Crystallography
Multidisciplinary
biology
Physics
Condensed Matter Physics
Cyclin-Dependent Kinases
Enzymes
Cell biology
CDC37
Physical Sciences
Crystal Structure
Protein Interaction Networks
Network Analysis
Research Article
Computer and Information Sciences
Protein Structure
Computational biology
Molecular Dynamics Simulation
Enzyme Regulation
03 medical and health sciences
Allosteric Regulation
Cyclin-dependent kinase
Solid State Physics
Humans
HSP90 Heat-Shock Proteins
Kinase activity
Molecular Biology
Cyclin-dependent kinase 5
lcsh:R
Biology and Life Sciences
Proteins
Models, Theoretical
030104 developmental biology
Allosteric enzyme
Chaperone (protein)
Enzymology
biology.protein
Cyclin-dependent kinase 9
lcsh:Q
Cyclin-dependent kinase 6
Protein Structure Networks
Protein Kinases
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 12
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....6ea966d36252d49ca10ab52d95a4d153