Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

Pau Creixell, Jai P. Pandey, Antonio Palmeri, Moitrayee Bhattacharyya, Marc Creixell, Rama Ranganathan, David Pincus, Michael B. Yaffe

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)371-383.e4
JournalCell Systems
Volume7
Issue number4
DOIs
StatePublished - Oct 24 2018

Fingerprint

Phosphotransferases
Substrate Specificity
Catalytic Domain
Signal Transduction
Pharmacology
Mutation
Neoplasms

Keywords

  • allosteric regulation
  • cancer mutations
  • catalysis
  • kinase
  • kinase inhibitors
  • substrate specificity

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Cite this

Creixell, P., Pandey, J. P., Palmeri, A., Bhattacharyya, M., Creixell, M., Ranganathan, R., ... Yaffe, M. B. (2018). Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. Cell Systems, 7(4), 371-383.e4. https://doi.org/10.1016/j.cels.2018.08.008

Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. / Creixell, Pau; Pandey, Jai P.; Palmeri, Antonio; Bhattacharyya, Moitrayee; Creixell, Marc; Ranganathan, Rama; Pincus, David; Yaffe, Michael B.

In: Cell Systems, Vol. 7, No. 4, 24.10.2018, p. 371-383.e4.

Research output: Contribution to journalArticle

Creixell, P, Pandey, JP, Palmeri, A, Bhattacharyya, M, Creixell, M, Ranganathan, R, Pincus, D & Yaffe, MB 2018, 'Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity', Cell Systems, vol. 7, no. 4, pp. 371-383.e4. https://doi.org/10.1016/j.cels.2018.08.008
Creixell P, Pandey JP, Palmeri A, Bhattacharyya M, Creixell M, Ranganathan R et al. Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. Cell Systems. 2018 Oct 24;7(4):371-383.e4. https://doi.org/10.1016/j.cels.2018.08.008
Creixell, Pau ; Pandey, Jai P. ; Palmeri, Antonio ; Bhattacharyya, Moitrayee ; Creixell, Marc ; Ranganathan, Rama ; Pincus, David ; Yaffe, Michael B. / Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. In: Cell Systems. 2018 ; Vol. 7, No. 4. pp. 371-383.e4.
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