ArticleProceedings of the National Academy of Sciences of the United States of America2019
Lipid-targeting pleckstrin homology domain turns its autoinhibitory face toward the TEC kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 28 citations in OpenAlex.
- More than an attachment module: covalent inhibitor warheads influence BTK dynamics and function.bioRxiv : the preprint server for biology · 2026Article
- Mechanism of activation of an ancestral TEC kinase by PIPNpj structural biology · 2026Article
- Article
- Regulatory mechanisms triggered by enzyme interactions with lipid membrane surfaces.Frontiers in molecular biosciences · 2023Review
- The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance.Journal of molecular biology · 2022Article
- Conformational switches that control the TEC kinase - PLCγ signaling axis.Journal of structural biology: X · 2022Review
- Evolution of Functional Diversity in the Holozoan Tyrosine Kinome.Molecular biology and evolution · 2021Article
- Hydrogen/Deuterium Exchange and Nuclear Magnetic Resonance Spectroscopy Reveal Dynamic Allostery on Multiple Time Scales in the Serine Protease Thrombin.Biochemistry · 2021Article
- A mechanism for localized dynamics-driven activation in Bruton's tyrosine kinase.Royal Society open science · 2021Article
- Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK.Frontiers in cell and developmental biology · 2021Review
- Differential impact of BTK active site inhibitors on the conformational state of full-length BTK.eLife · 2020Article
- Conformational states dynamically populated by a kinase determine its function.Science (New York, N.Y.) · 2020Article
- Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling.International journal of molecular sciences · 2020Review
- Novel roles of phosphoinositides in signaling, lipid transport, and disease.Current opinion in cell biology · 2020Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The pleckstrin homology (PH) domain is well known for its phospholipid targeting function. The PH-TEC homology (PHTH) domain within the TEC family of tyrosine kinases is also a crucial component of the autoinhibitory apparatus. The autoinhibitory surface on the PHTH domain has been previously defined, and biochemical investigations have shown that PHTH-mediated inhibition is mutually exclusive with phosphatidylinositol binding. Here we use hydrogen/deuterium exchange mass spectrometry, nuclear magnetic resonance (NMR), and evolutionary sequence comparisons to map where and how the PHTH domain affects the Bruton's tyrosine kinase (BTK) domain. The data map a PHTH-binding site on the activation loop face of the kinase C lobe, suggesting that the PHTH domain masks the activation loop and the substrate-docking site. Moreover, localized NMR spectral changes are observed for non-surface-exposed residues in the active site and on the distal side of the kinase domain. These data suggest that the association of PHTH induces allosteric conformational shifts in regions of the kinase domain that are critical for catalysis. Through statistical comparisons of diverse tyrosine kinase sequences, we identify residues unique to BTK that coincide with the experimentally determined PHTH-binding surface on the kinase domain. Our data provide a more complete picture of the autoinhibitory conformation adopted by full-length TEC kinases, creating opportunities to target the regulatory domains to control the function of these kinases in a biological setting.
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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 Socratic graph.