ArticleThe EMBO journal2006
A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases.
Article in The EMBO journal, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 105 citations in OpenAlex.
- Article
- Structures of KEOPS bound to tRNA reveal functional roles of the kinase Bud32.Nature communications · 2024Article
- Article
- Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.bioRxiv : the preprint server for biology · 2024Article
- Article
- Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.Nature communications · 2023Article
- EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Angiogenesis depends upon EPHB4-mediated export of collagen IV from vascular endothelial cells.JCI insight · 2022Article
- Roles of Eph-Ephrin Signaling in the Eye Lens Cataractogenesis, Biomechanics, and Homeostasis.Frontiers in cell and developmental biology · 2022Review
- Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies.Pharmaceuticals (Basel, Switzerland) · 2021Article
- The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs.The Biochemical journal · 2021Article
- Article
- The EphB6 Receptor: Kinase-Dead but Very Much Alive.International journal of molecular sciences · 2021Review
- A regulatory role of membrane by direct modulation of the catalytic kinase domain.Small GTPases · 2021Review
- Conformational states dynamically populated by a kinase determine its function.Science (New York, N.Y.) · 2020Article
- Two-step release of kinase autoinhibition in discoidin domain receptor 1.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Microsecond dynamics in proteins by two-dimensional ESR: Predictions.The Journal of chemical physics · 2020Article
- NMR and computational methods for molecular resolution of allosteric pathways in enzyme complexes.Biophysical reviews · 2020Review
- A Dynamic Switch in Inactive p38γ Leads to an Excited State on the Pathway to an Active Kinase.Biochemistry · 2019Article
- Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations.ACS omega · 2019Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Eph receptor tyrosine kinases (RTKs) mediate numerous developmental processes. Their activity is regulated by auto-phosphorylation on two tyrosines within the juxtamembrane segment (JMS) immediately N-terminal to the kinase domain (KD). Here, we probe the molecular details of Eph kinase activation through mutational analysis, X-ray crystallography and NMR spectroscopy on auto-inhibited and active EphB2 and EphA4 fragments. We show that a Tyr750Ala gain-of-function mutation in the KD and JMS phosphorylation independently induce disorder of the JMS and its dissociation from the KD. Our X-ray analyses demonstrate that this occurs without major conformational changes to the KD and with only partial ordering of the KD activation segment. However, conformational exchange for helix alphaC in the N-terminal KD lobe and for the activation segment, coupled with increased inter-lobe dynamics, is observed upon kinase activation in our NMR analyses. Overall, our results suggest that a change in inter-lobe dynamics and the sampling of catalytically competent conformations for helix alphaC and the activation segment rather than a transition to a static active conformation underlies Eph RTK activation.
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Registered trials
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.