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- W4249207002 abstract "The diphtheria toxin T-domain translocates the catalytic C-domain across the endosomal membrane in response to acidification. To elucidate the role of histidine protonation in modulating pH-dependent membrane action of the T-domain, we have used site-directed mutagenesis coupled with spectroscopic and physiological assays. Our studies revealed several patterns of membrane action caused by replacements of various histidines, implying differential role of histidine protonation in T-domain functioning. Replacement of H257 with an arginine (but not with a glutamine) resulted in dramatic unfolding of the protein at neutral pH, accompanied by a substantial loss of helical structure and greatly increased exposure of the buried residues, W206 and W281. This unfolding and spectral shift could be reversed by the interaction of the H257R mutant with model lipid membranes. Remarkably, this greatly unfolded mutant exhibited WT-like activity in channel formation, N-terminus translocation, and cytotoxicity assays. Moreover, membrane permeabilization caused by H257R mutant occurs already at pH 6, where wild type protein is inactive. In contrast, replacing all three histidines in the C-terminus domain (H322, H323, H372) with either neutral (triple-Q mutant) or charged (triple-R mutant) residues does not result in any alterations in solution fold (judged by CD and intrinsic fluorescence data) nor in insertion of the TH8-9 helical hairpin (judged by spectroscopic responses of selectively attached external dyes); nevertheless, this produces functionally impaired mutants. We conclude that protonation of H257 acts as a major component of the pH-dependent conformational switch, resulting in destabilization of the folded structure in solution and thereby promoting the initial membrane interactions necessary for translocation. Supported by NIH GM069783(-04S1)." @default.
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- W4249207002 date "2011-02-01" @default.
- W4249207002 modified "2023-09-30" @default.
- W4249207002 title "Conformational Switching of the Diphtheria Toxin T-Domain" @default.
- W4249207002 doi "https://doi.org/10.1016/j.bpj.2010.12.254" @default.
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