Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity
Mycolactone is an exotoxin produced by <i>Mycobacterium ulcerans</i> that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing several secretory and transmembrane prote...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/15/8/486 |
| _version_ | 1797583115523194880 |
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| author | John D. M. Nguyen Gabriel C. A. da Hora Jessica M. J. Swanson |
| author_facet | John D. M. Nguyen Gabriel C. A. da Hora Jessica M. J. Swanson |
| author_sort | John D. M. Nguyen |
| collection | DOAJ |
| description | Mycolactone is an exotoxin produced by <i>Mycobacterium ulcerans</i> that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing several secretory and transmembrane proteins, resulting in cytotoxic and immunomodulatory effects. Interestingly, only one of the two dominant isoforms of mycolactone is cytotoxic. Here, we investigate the origin of this specificity by performing extensive molecular dynamics (MD) simulations with enhanced free energy sampling to query the association trends of the two isoforms with both the Sec61 translocon, using two distinct cryo-electron microscopy (cryo-EM) models as references, and the ER membrane, which serves as a toxin reservoir prior to association. Our results suggest that mycolactone B (the cytotoxic isoform) has a stronger association with the ER membrane than mycolactone A due to more favorable interactions with membrane lipids and water molecules. This could increase the reservoir of toxin proximal to the Sec61 translocon. In one model of Sec61 inhibited by mycolactone, we find that isomer B interacts more closely with residues thought to play a key role in signal peptide recognition and, thus, are essential for subsequent protein translocation. In the other model, we find that isomer B interacts more closely with the lumenal and lateral gates of the translocon, the dynamics of which are essential for protein translocation. These interactions induce a more closed conformation, which has been suggested to block signal peptide insertion and subsequent protein translocation. Collectively, these findings suggest that isomer B’s unique cytotoxicity is a consequence of both increased localization to the ER membrane and channel-locking association with the Sec61 translocon, facets that could be targeted in the development of Buruli Ulcer diagnostics and Sec61-targeted therapeutics. |
| first_indexed | 2024-03-10T23:31:18Z |
| format | Article |
| id | doaj.art-10d4da25abf74954a193e0545b81f5eb |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-10T23:31:18Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-10d4da25abf74954a193e0545b81f5eb2023-11-19T03:15:17ZengMDPI AGToxins2072-66512023-08-0115848610.3390/toxins15080486Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific ToxicityJohn D. M. Nguyen0Gabriel C. A. da Hora1Jessica M. J. Swanson2Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USADepartment of Chemistry, University of Utah, Salt Lake City, UT 84112, USADepartment of Chemistry, University of Utah, Salt Lake City, UT 84112, USAMycolactone is an exotoxin produced by <i>Mycobacterium ulcerans</i> that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing several secretory and transmembrane proteins, resulting in cytotoxic and immunomodulatory effects. Interestingly, only one of the two dominant isoforms of mycolactone is cytotoxic. Here, we investigate the origin of this specificity by performing extensive molecular dynamics (MD) simulations with enhanced free energy sampling to query the association trends of the two isoforms with both the Sec61 translocon, using two distinct cryo-electron microscopy (cryo-EM) models as references, and the ER membrane, which serves as a toxin reservoir prior to association. Our results suggest that mycolactone B (the cytotoxic isoform) has a stronger association with the ER membrane than mycolactone A due to more favorable interactions with membrane lipids and water molecules. This could increase the reservoir of toxin proximal to the Sec61 translocon. In one model of Sec61 inhibited by mycolactone, we find that isomer B interacts more closely with residues thought to play a key role in signal peptide recognition and, thus, are essential for subsequent protein translocation. In the other model, we find that isomer B interacts more closely with the lumenal and lateral gates of the translocon, the dynamics of which are essential for protein translocation. These interactions induce a more closed conformation, which has been suggested to block signal peptide insertion and subsequent protein translocation. Collectively, these findings suggest that isomer B’s unique cytotoxicity is a consequence of both increased localization to the ER membrane and channel-locking association with the Sec61 translocon, facets that could be targeted in the development of Buruli Ulcer diagnostics and Sec61-targeted therapeutics.https://www.mdpi.com/2072-6651/15/8/486mycolactoneBuruli ulcerER membraneSec61 transloconmolecular dynamicsmembrane permeation |
| spellingShingle | John D. M. Nguyen Gabriel C. A. da Hora Jessica M. J. Swanson Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity Toxins mycolactone Buruli ulcer ER membrane Sec61 translocon molecular dynamics membrane permeation |
| title | Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity |
| title_full | Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity |
| title_fullStr | Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity |
| title_full_unstemmed | Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity |
| title_short | Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity |
| title_sort | mycolactone a vs b multiscale simulations reveal the roles of localization and association in isomer specific toxicity |
| topic | mycolactone Buruli ulcer ER membrane Sec61 translocon molecular dynamics membrane permeation |
| url | https://www.mdpi.com/2072-6651/15/8/486 |
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