Structural investigation of Tc toxin activation
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Date
2025
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Abstract
Tc toxins represent a potent class of bacterial protein toxins, with molecular complexes reaching up to 2 MDa. Their exceptional size both protects toxic effectors and makes them one of the largest known protein translocation systems inserting into host membranes. Due to their adaptability, Tc toxins have gained interest for translational applications, including biopesticides and molecular delivery systems. However, the molecular basis of their interaction with host cells remains poorly understood. In this work, I applied an integrative structural biology approach, combining cryo-electron microscopy, cryo-electron tomography, light microscopy, and molecular dynamics simulations, to elucidate Tc toxin function. Using high-resolution structures of Photorhabdus luminescens Tc mutants, we uncovered a conserved mechanism for pH-dependent pore formation, mediated by an electrostatically regulated molecular latch. Further analysis of Yersinia entomophaga Tc (YenTc) revealed novel conformational states, indicating that outer shell rearrangements confer structural versatility across split-A Tc toxins. To connect structural dynamics with cellular activity, I developed a fluorescent reporter assay that monitors endosomal maturation in single cells, enabling direct correlation with electron microscopy imaging of Tc toxin entry. Together, these findings provide molecular insights into Tc toxin action and establish new tools for dissecting their cellular uptake, thereby facilitating future efforts to adapt Tc toxins for biomedical and agricultural applications.
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Keywords
Tc toxins, Structural biology, Cryo-EM, Mechanistic insights, Pore formation, Host interaction, Infection
Subjects based on RSWK
Strukturbiologie, Kryoelektronenmikroskopie, Infektion