MIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

Author(s)
Creixell, Pau; Pandey, Jai P.; Creixell, Marc; Pincus, David; Yaffe, Michael B.
Thumbnail
DownloadPublished version (6.910Mb)
Publisher with Creative Commons License

Publisher with Creative Commons License

Creative Commons Attribution

Terms of use
Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/
Metadata
Show full item record
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.
Date issued
2018-10
URI
https://hdl.handle.net/1721.1/124648
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
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
ISSN
2405-4712

Collections
  • MIT Open Access Articles

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries
PrivacyPermissionsAccessibilityContact us
MIT
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.