Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

• Main Authors: Creixell, Pau (Author), Pandey, Jai P. (Author), Creixell, Marc (Author), Pincus, David (Author), Yaffe, Michael B. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Whitehead Institute for Biomedical Research (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-04-15T13:00:15Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institutes of Health (U.S.) (Early Independence Award DP5 OD017941)
National Institutes of Health (U.S.) (Grant CA226393)
National Institutes of Health (U.S.) (Grant GM104047)
National Institutes of Health (U.S.) (Grant ES015339)
National Institutes of Health (U.S.) (Grant ES028374)