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- W4255756494 abstract "Protein side chain protonation, coupled to conformational rearrangements, is one way of regulating physiological function caused by changes in protein environment. Specifically, protonation of histidine residues has been implicated in pH-dependent conformational switching in several systems, including the diphtheria toxin translocation (T) domain, responsible for the toxin's cellular entry via the endosomal pathway. Our previous studies (a) identified protonation of H257 as a major component of the T domain's conformational switch and (b) suggested the possibility of a neighboring H223 acting as a modulator, affecting the protonation of H257 and preventing premature conformational changes outside the endosome. To verify this “safety latch” hypothesis, we report here the pH-dependent folding and membrane interactions of the T domain wild type and that of the H223Q mutant, lacking the latch. Thermal unfolding of the T domain, measured by circular dichroism, revealed that the reduction in the transition temperature for helical unfolding for an H223Q mutant starts at less acidic conditions (pH < 7.5) relative to the wild type protein (pH < 6.5). Hydrogen-deuterium exchange mass spectrometry demonstrates the H223Q replacement results in a loss of stability of the amphipathic helices TH1-3 and the hydrophobic core helix TH8 at pH 6.5. This destabilization occurring in solution correlates well with the pH-range shift for the onset of the membrane permeabilization and translocation activity of the T domain, confirming our initial hypothesis that H223 protonation guards against early refolding. Taken together, these results demonstrate that histidine protonation can fine-tune pH-dependent switching in physiologically-relevant systems." @default.
- W4255756494 created "2022-05-12" @default.
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- W4255756494 date "2017-02-01" @default.
- W4255756494 modified "2023-09-27" @default.
- W4255756494 title "The pH-Dependent Trigger in Diphtheria Toxin T Domain Comes with a Safety Latch" @default.
- W4255756494 doi "https://doi.org/10.1016/j.bpj.2016.11.1023" @default.
- W4255756494 hasPublicationYear "2017" @default.
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