ArticlePloS one2015
Co-conserved MAPK features couple D-domain docking groove to distal allosteric sites via the C-terminal flanking tail.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- Mapping of dynamic allostery within p38 alpha kinase via network analyses and NMR spectroscopy.Nature communications · 2026Article
- Evolutionary analysis through structural modeling of FAM222 proteins reveals a novel disordered conserved domain in vertebrates that interacts with NLK.Scientific reports · 2025Article
- TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas.Neuro-oncology · 2025Article
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- Mechanistic and evolutionary insights into isoform-specific 'supercharging' in DCLK family kinases.eLife · 2023Article
- Article
- EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression.iScience · 2022Article
- A walk-through MAPK structure and functionality with the 30-year-old yeast MAPK Slt2.International microbiology : the official journal of the Spanish Society for Microbiology · 2021Review
- Specific Functional Features of the Cell Integrity MAP Kinase Pathway in the Dimorphic Fission YeastJournal of fungi (Basel, Switzerland) · 2021Article
- Cataloguing the dead: breathing new life into pseudokinase research.The FEBS journal · 2020Review
- Kinase Activation by Small Conformational Changes.Journal of chemical information and modeling · 2020Article
- Quorum sensing and stress-activated MAPK signaling repress yeast to hypha transition in the fission yeast Schizosaccharomyces japonicus.PLoS genetics · 2019Article
- Coupled regulation by the juxtamembrane and sterile α motif (SAM) linker is a hallmark of ephrin tyrosine kinase evolution.The Journal of biological chemistry · 2018Article
- Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease.Trends in cell biology · 2017Review
- JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships.Microbiology and molecular biology reviews : MMBR · 2016Review
- Tighter αC-helix-αL16-helix interactions seem to make p38α less prone to activation by autophosphorylation than Hog1.Bioscience reports · 2016Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitogen activated protein kinases (MAPKs) form a closely related family of kinases that control critical pathways associated with cell growth and survival. Although MAPKs have been extensively characterized at the biochemical, cellular, and structural level, an integrated evolutionary understanding of how MAPKs differ from other closely related protein kinases is currently lacking. Here, we perform statistical sequence comparisons of MAPKs and related protein kinases to identify sequence and structural features associated with MAPK functional divergence. We show, for the first time, that virtually all MAPK-distinguishing sequence features, including an unappreciated short insert segment in the β4-β5 loop, physically couple distal functional sites in the kinase domain to the D-domain peptide docking groove via the C-terminal flanking tail (C-tail). The coupling mediated by MAPK-specific residues confers an allosteric regulatory mechanism unique to MAPKs. In particular, the regulatory αC-helix conformation is controlled by a MAPK-conserved salt bridge interaction between an arginine in the αC-helix and an acidic residue in the C-tail. The salt-bridge interaction is modulated in unique ways in individual sub-families to achieve regulatory specificity. Our study is consistent with a model in which the C-tail co-evolved with the D-domain docking site to allosterically control MAPK activity. Our study provides testable mechanistic hypotheses for biochemical characterization of MAPK-conserved residues and new avenues for the design of allosteric MAPK inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.