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- W2789643726 abstract "The conversion of a protein structure from a water-soluble to membrane-inserted form is one of the least understood cellular processes. In many cases this transition is triggered by the changes in side-chain protonation. Examples include cellular action of various bacterial toxins and of multiple proteins of the Bcl-2 family of apoptotic regulators. Here we use an array of tools of fluorescence spectroscopy to compare and contrast membrane insertion of the two structurally similar, but functionally unrelated, representatives from these families: (a) the diphtheria toxin translocation (T) domain and (b) anti-apoptotic regulator Bcl-xL. Our results indicate that insertion pathway of the T-domain contains two staggered pH-dependent transitions and that several key protonatable residues (e.g., H223, H257, H322, E362) play important roles in conformational switching. The redundancy of conformational switching in T-domain correlates well with its physiological function to ensure robust translocation of the catalytic moiety of the toxin across the bilayer in response to acidification of the endosome. In contrast, bilayer-mediated interactions of the Bcl-2 family are tightly regulated to produce inhibition of mitochondrial outer membrane permeation (MOMP) under normal conditions and trigger MOMP in apoptosis. We hypothesize that changes in lipid composition modulate the balance of cell death and survival by causing conformational switching in Bcl-2 proteins. For Bcl-xL, this modulation can be seen by the effects of physicochemical properties of the lipid bilayer interface on the switching between anchored and inserted conformations involved in different modes of MOMP inhibition. Our results indicate that while T-domain of the diphtheria toxin and Bcl-xL share some architectural similarities along the insertion pathway, their modes of conformational switching are distinctly different: T-domain is switched via actual changes in pH, while Bcl-xL is switched via lipid-dependent changes in pKa at constant pH. NIH:P30-GM110761." @default.
- W2789643726 created "2018-03-29" @default.
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- W2789643726 date "2018-02-01" @default.
- W2789643726 modified "2023-09-25" @default.
- W2789643726 title "Lipid-Dependent Modulation of Conformational Switching by Protonation during Membrane Protein Insertion" @default.
- W2789643726 doi "https://doi.org/10.1016/j.bpj.2017.11.1349" @default.
- W2789643726 hasPublicationYear "2018" @default.
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