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Cell Syst. 2018 Oct 24;7(4):371-383.e4. doi: 10.1016/j.cels.2018.08.008. Epub 2018 Sep 19.

Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3
Viale Lido 94, 96012 Avola, Italy.
4
Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
5
Center for Physics of Evolving Systems, Department of Biochemistry and Molecular Biology, Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
6
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: pincus@wi.mit.edu.
7
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Divisions of Acute Care Surgery, Trauma, and Critical Care and Surgical Oncology, Harvard Medical School, Boston 02215, USA. Electronic address: myaffe@mit.edu.

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.

KEYWORDS:

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

PMID:
30243563
PMCID:
PMC6202253
[Available on 2019-10-24]
DOI:
10.1016/j.cels.2018.08.008
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