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Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism
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 proces...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219829/ https://www.ncbi.nlm.nih.gov/pubmed/34158520 http://dx.doi.org/10.1038/s41598-021-91596-3 |
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author | Machen, Alexandra J. Fisher, Mark T. Freudenthal, Bret D. |
author_facet | Machen, Alexandra J. Fisher, Mark T. Freudenthal, Bret D. |
author_sort | Machen, Alexandra J. |
collection | PubMed |
description | 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 PA(pore) translocating the N-terminal domain of LF (LF(N)). The resulting 3.3 Å structure of the complex shows density of partially unfolded LF(N) near the canonical PA(pore) 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 | Online Article Text |
id | pubmed-8219829 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82198292021-06-24 Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism Machen, Alexandra J. Fisher, Mark T. Freudenthal, Bret D. Sci Rep Article 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 PA(pore) translocating the N-terminal domain of LF (LF(N)). The resulting 3.3 Å structure of the complex shows density of partially unfolded LF(N) near the canonical PA(pore) 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. Nature Publishing Group UK 2021-06-22 /pmc/articles/PMC8219829/ /pubmed/34158520 http://dx.doi.org/10.1038/s41598-021-91596-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Machen, Alexandra J. Fisher, Mark T. Freudenthal, Bret D. Anthrax toxin translocation complex reveals insight into the lethal factor unfolding and refolding mechanism |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219829/ https://www.ncbi.nlm.nih.gov/pubmed/34158520 http://dx.doi.org/10.1038/s41598-021-91596-3 |
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