Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity
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1-s2.0-S2405471218303557-main.pdf
Description
Published version
Size
6.91 MB
Format
Adobe PDF
Checksum (MD5)
1c31f0203c87896950b8f67005d4c5f9
Author(s)
Creixell, Pau
Pandey, Jai P.
Creixell, Marc
Pincus, David
Yaffe, Michael B.
Date Issued
October 2018
Journal
Cell Systems
Publisher
Elsevier BV
Citation
Creixell, Pau et al. "Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity." Cell Systems 7 (2018): 371-383 © 2018 The Author(s)
Version
Final published version
Abstract
The functional diversity of kinases enables specificity in cellular signal transduction. Yet how more than 500 members of the human kinome specifically receive regulatory inputs and convey information to appropriate substrates—all while using the common signaling output of phosphorylation—remains enigmatic. Here, we perform statistical co-evolution analysis, mutational scanning, and quantitative live-cell assays to reveal a hierarchical organization of the kinase domain that facilitates the orthogonal evolution of regulatory inputs and substrate outputs while maintaining catalytic function. We find that three quasi-independent “sectors”—groups of evolutionarily coupled residues—represent functional units in the kinase domain that encode for catalytic activity, substrate specificity, and regulation. Sector positions impact both disease and pharmacology: the catalytic sector is significantly enriched for somatic cancer mutations, and residues in the regulatory sector interact with allosteric kinase inhibitors. We propose that this functional architecture endows the kinase domain with inherent regulatory plasticity. Creixell et al. describe three quasi-independent “sectors”—groups of evolutionarily coupled amino acids—in the kinase domain that determine catalytic activity, substrate specificity, and regulatory interactions. The sectors are differentially utilized by subgroups of kinases and may help explain how the kinase domain evolved diverse regulatory inputs and substrate outputs.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Biological Engineering
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1016/j.cels.2018.08.008
