Role of the α Clamp in the Protein Translocation Mechanism of Anthrax Toxin

Journal of Molecular Biology
Michael J BrownBryan A Krantz

Abstract

Membrane-embedded molecular machines are utilized to move water-soluble proteins across these barriers. Anthrax toxin forms one such machine through the self-assembly of its three component proteins--protective antigen (PA), lethal factor, and edema factor. Upon endocytosis into host cells, acidification of the endosome induces PA to form a membrane-inserted channel, which unfolds lethal factor and edema factor and translocates them into the host cytosol. Translocation is driven by the proton motive force, composed of the chemical potential, the proton gradient (ΔpH), and the membrane potential (Δψ). A crystal structure of the lethal toxin core complex revealed an "α clamp" structure that binds to substrate helices nonspecifically. Here, we test the hypothesis that, through the recognition of unfolding helical structure, the α clamp can accelerate the rate of translocation. We produced a synthetic PA mutant in which an α helix was crosslinked into the α clamp to block its function. This synthetic construct impairs translocation by raising a yet uncharacterized translocation barrier shown to be much less force dependent than the known unfolding barrier. We also report that the α clamp more stably binds substrates that can form h...Continue Reading

Citations

May 27, 2017·Critical Reviews in Biochemistry and Molecular Biology·Kathleen E OrrellRoman A Melnyk
Jan 25, 2017·Journal of Molecular Biology·Debasis Das, Bryan A Krantz
Sep 28, 2016·The Journal of General Physiology·Lucien FabreIsabelle Rouiller
Mar 4, 2020·Nature Structural & Molecular Biology·Tomohito YamadaHideaki Tsuge
Dec 15, 2015·Pathogens and Disease·Sergey M Bezrukov, Ekaterina M Nestorovich
Aug 24, 2020·Archives of Biochemistry and Biophysics·Suet Y LoStefan Siemann

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