Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism

Abstract Translocation is essential to the anthrax toxin mechanism. Protective antigen (PA), the binding component of this AB toxin, forms an oligomeric pore that translocates lethal factor (LF) or edema factor, the active components of the toxin, into the cell. Structural details of the translocati...

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Autores principales:	Alexandra J. Machen, Mark T. Fisher, Bret D. Freudenthal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3f8e058c49e347208faec432f78c2113
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spelling	oai:doaj.org-article:3f8e058c49e347208faec432f78c21132021-12-02T17:45:17ZAnthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism10.1038/s41598-021-91596-32045-2322https://doaj.org/article/3f8e058c49e347208faec432f78c21132021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91596-3https://doaj.org/toc/2045-2322Abstract Translocation is essential to the anthrax toxin mechanism. Protective antigen (PA), the binding component of this AB toxin, forms an oligomeric pore that translocates lethal factor (LF) or edema factor, the active components of the toxin, into the cell. Structural details of the translocation process have remained elusive despite their biological importance. To overcome the technical challenges of studying translocation intermediates, we developed a method to immobilize, transition, and stabilize anthrax toxin to mimic important physiological steps in the intoxication process. Here, we report a cryoEM snapshot of PApore translocating the N-terminal domain of LF (LFN). The resulting 3.3 Å structure of the complex shows density of partially unfolded LFN near the canonical PApore binding site. Interestingly, we also observe density consistent with an α helix emerging from the 100 Å β barrel channel suggesting LF secondary structural elements begin to refold in the pore channel. We conclude the anthrax toxin β barrel aids in efficient folding of its enzymatic payload prior to channel exit. Our hypothesized refolding mechanism has broader implications for pore length of other protein translocating toxins.Alexandra J. MachenMark T. FisherBret D. FreudenthalNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alexandra J. Machen Mark T. Fisher Bret D. Freudenthal Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
description	Abstract Translocation is essential to the anthrax toxin mechanism. Protective antigen (PA), the binding component of this AB toxin, forms an oligomeric pore that translocates lethal factor (LF) or edema factor, the active components of the toxin, into the cell. Structural details of the translocation process have remained elusive despite their biological importance. To overcome the technical challenges of studying translocation intermediates, we developed a method to immobilize, transition, and stabilize anthrax toxin to mimic important physiological steps in the intoxication process. Here, we report a cryoEM snapshot of PApore translocating the N-terminal domain of LF (LFN). The resulting 3.3 Å structure of the complex shows density of partially unfolded LFN near the canonical PApore binding site. Interestingly, we also observe density consistent with an α helix emerging from the 100 Å β barrel channel suggesting LF secondary structural elements begin to refold in the pore channel. We conclude the anthrax toxin β barrel aids in efficient folding of its enzymatic payload prior to channel exit. Our hypothesized refolding mechanism has broader implications for pore length of other protein translocating toxins.
format	article
author	Alexandra J. Machen Mark T. Fisher Bret D. Freudenthal
author_facet	Alexandra J. Machen Mark T. Fisher Bret D. Freudenthal
author_sort	Alexandra J. Machen
title	Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
title_short	Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
title_full	Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
title_fullStr	Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
title_full_unstemmed	Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
title_sort	anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3f8e058c49e347208faec432f78c2113
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Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism

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