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Histidine Protonation and Conformational Switching in Diphtheria Toxin Translocation Domain.
Toxins (Basel)
June 2023
Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA.
Protonation of key histidine residues has been long implicated in the acid-mediated cellular action of the diphtheria toxin translocation (T-) domain, responsible for the delivery of the catalytic domain into the cell. Here, we use a combination of computational (constant-pH Molecular Dynamics simulations) and experimental (NMR, circular dichroism, and fluorescence spectroscopy along with the X-ray crystallography) approaches to characterize the initial stages of conformational change happening in solution in the wild-type T-domain and in the H223Q/H257Q double mutant. This replacement suppresses the acid-induced transition, resulting in the retention of a more stable protein structure in solutions at pH 5.
View Article and Find Full Text PDFCpG 1018® adjuvant enhances Tdap immune responses against Bordetella pertussis in mice.
Vaccine
August 2022
Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, USA; Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA. Electronic address:
Bordetella pertussis is the causative agent of whooping cough (pertussis), a severe respiratory disease that can be fatal, particularly in infants. Despite high vaccine coverage, pertussis remains a problem because the currently used DTaP and Tdap vaccines do not completely prevent infection or transmission. It is well established that the alum adjuvant is a potential weakness of the acellular vaccines because the immunity provided by it is short-term.
View Article and Find Full Text PDFCharacterization of a flexible AAV-DTR/DT mouse model of acute epithelial lung injury.
Am J Physiol Lung Cell Mol Physiol
August 2022
Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Animal models are important to mimic certain pathways or biological aspects of human pathologies including acute and chronic pulmonary diseases. We developed a novel and flexible mouse model of acute epithelial lung injury based on adeno-associated virus (AAV) variant 6.2-mediated expression of the human diphtheria toxin receptor (DTR).
View Article and Find Full Text PDFLeveraging serology to titrate immunisation programme functionality for diphtheria in Madagascar.
Epidemiol Infect
January 2022
Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA.
Diphtheria is a potentially devastating disease whose epidemiology remains poorly described in many settings, including Madagascar. Diphtheria vaccination is delivered in combination with pertussis and tetanus antigens and coverage of this vaccine is often used as a core measure of health system functioning. However, coverage is challenging to estimate due to the difficulty in translating numbers of doses delivered into numbers of children effectively immunised.
View Article and Find Full Text PDFReaction intermediate rotation during the decarboxylation of coproheme to heme b in C. diphtheriae.
Biophys J
September 2021
Dipartimento di Chimica "Ugo Schiff", Università di Firenze, Sesto Fiorentino (FI), Italy; INSTM Research Unit of Firenze, Sesto Fiorentino, Italy. Electronic address:
Monoderm bacteria utilize coproheme decarboxylases (ChdCs) to generate heme b by a stepwise decarboxylation of two propionate groups of iron coproporphyrin III (coproheme), forming two vinyl groups. This work focuses on actinobacterial ChdC from Corynebacterium diphtheriae (CdChdC) to elucidate the hydrogen peroxide-mediated decarboxylation of coproheme via monovinyl monopropionyl deuteroheme (MMD) to heme b, with the principal aim being to understand the reorientation mechanism of MMD during turnover. Wild-type CdChdC and variants, namely H118A, H118F, and A207E, were studied by resonance Raman and ultraviolet-visible spectroscopy, mass spectrometry, and molecular dynamics simulations.
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