ArticleBiochemistry2014
Hydrogen-deuterium exchange and mass spectrometry reveal the pH-dependent conformational changes of diphtheria toxin T domain.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 39 citations in OpenAlex.
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- Activation mechanism of small heat shock protein HSPB5 revealed by disease-associated mutants.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Recalibrating Protection Factors Using Millisecond Hydrogen/Deuterium Exchange Mass Spectrometry.Analytical chemistry · 2025Article
- Hybrid Mass Spectrometry Applied across the Production of Antibody Biotherapeutics.Journal of the American Society for Mass Spectrometry · 2025Article
- GPR180 is a new member of the Golgi-dynamics domain seven-transmembrane helix protein family.Communications biology · 2024Article
- Therapeutic Application and Structural Features of Adeno-Associated Virus Vector.Current issues in molecular biology · 2024Review
- MgbioRxiv : the preprint server for biology · 2024Article
- Hydrogen/Deuterium Exchange Mass Spectrometry Provides Insights into the Role of Drosophila Testis-Specific Myosin VI Light Chain AndroCaM.Biochemistry · 2024Article
- Joint X-ray/neutron structure of Lentinus similis AA9_A at room temperature.Acta crystallographica. Section F, Structural biology communications · 2023Article
- HDfleX: Software for Flexible High Structural Resolution of Hydrogen/Deuterium-Exchange Mass Spectrometry Data.Analytical chemistry · 2022Article
- THE MAKING OF A FOOTPRINT IN PROTEIN FOOTPRINTING: A REVIEW IN HONOR OF MICHAEL L. GROSS.Mass spectrometry reviews · 2021Review
- Conformational switching, refolding and membrane insertion of the diphtheria toxin translocation domain.Methods in enzymology · 2021Article
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- Calcium Binding to the Innate Immune Protein Human Calprotectin Revealed by Integrated Mass Spectrometry.Journal of the American Chemical Society · 2020Article
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- Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody.Structure (London, England : 1993) · 2019Article
- Pulsed Hydrogen-Deuterium Exchange Illuminates the Aggregation Kinetics of α-Synuclein, the Causative Agent for Parkinson's Disease.ACS chemical neuroscience · 2018Article
- Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The translocation (T) domain of diphtheria toxin plays a critical role in moving the catalytic domain across the endosomal membrane. Translocation/insertion is triggered by a decrease in pH in the endosome where conformational changes of T domain occur through several kinetic intermediates to yield a final trans-membrane form. High-resolution structural studies are only applicable to the static T-domain structure at physiological pH, and studies of the T-domain translocation pathway are hindered by the simultaneous presence of multiple conformations. Here, we report the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) for the study of the pH-dependent conformational changes of the T domain in solution. Effects of pH on intrinsic HDX rates were deconvolved by converting the on-exchange times at low pH into times under our "standard condition" (pH 7.5). pH-Dependent HDX kinetic analysis of T domain clearly reveals the conformational transition from the native state (W-state) to a membrane-competent state (W(+)-state). The initial transition occurs at pH 6 and includes the destabilization of N-terminal helices accompanied by the separation between N- and C-terminal segments. The structural rearrangements accompanying the formation of the membrane-competent state expose a hydrophobic hairpin (TH8-9) to solvent, prepare it to insert into the membrane. At pH 5.5, the transition is complete, and the protein further unfolds, resulting in the exposure of its C-terminal hydrophobic TH8-9, leading to subsequent aggregation in the absence of membranes. This solution-based study complements high resolution crystal structures and provides a detailed understanding of the pH-dependent structural rearrangement and acid-induced oligomerization of T domain.
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