ArticleCell systems2018
Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity.
Article in Cell systems, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- A Constellation of Fluorescent Biosensors to Illuminate the Galaxy of Protein Kinases.Chembiochem : a European journal of chemical biology · 2026Review
- The allosteric landscape of the Src kinase.Science advances · 2026Article
- Recent breakthroughs in understanding the allosteric features of Ras GTPases and their effector and regulatory protein interactions, enabling drug design.Current opinion in structural biology · 2026Review
- Critical role of the CMGC insert sequence for tyrosine autophosphorylation in the protein kinase DYRK1B.Scientific reports · 2025Article
- Article
- Recurring EPHB1 mutations in human cancers alter receptor signalling and compartmentalisation of colorectal cancer cells.Cell communication and signaling : CCS · 2023Article
- CDK6 activity in a recurring convergent kinase network motif.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Revealing enzyme functional architecture via high-throughput microfluidic enzyme kinetics.Science (New York, N.Y.) · 2021Article
- Article
- Both intra and inter-domain interactions define the intrinsic dynamics and allosteric mechanism in DNMT1s.Computational and structural biotechnology journal · 2020Article
- Mass Spectrometry-Based Discovery ofMass spectrometry (Tokyo, Japan) · 2020Article
- Surveying the Side-Chain Network Approach to Protein Structure and Dynamics: The SARS-CoV-2 Spike Protein as an Illustrative Case.Frontiers in molecular biosciences · 2020Review
- aPKC in neuronal differentiation, maturation and function.Neuronal signaling · 2019Review
- Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output.PLoS biology · 2019Article
- Understanding molecular mechanisms in cell signaling through natural and artificial sequence variation.Nature structural & molecular biology · 2019Review
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8 authors.
Funding
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.
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