dc.contributor.author | Rodnin, Mykola V. | |
dc.contributor.author | Kashipathy, Maithri M. | |
dc.contributor.author | Kyrychenko, Alexander | |
dc.contributor.author | Battaile, Kevin P. | |
dc.contributor.author | Lovell, Scott | |
dc.contributor.author | Ladokhin, Alexey S. | |
dc.date.accessioned | 2020-12-14T20:27:19Z | |
dc.date.available | 2020-12-14T20:27:19Z | |
dc.date.issued | 2020-11-07 | |
dc.identifier.citation | Rodnin, M. V., Kashipathy, M. M., Kyrychenko, A., Battaile, K. P., Lovell, S., & Ladokhin, A. S. (2020). Structure of the Diphtheria Toxin at Acidic pH: Implications for the Conformational Switching of the Translocation Domain. Toxins, 12(11), 704. https://doi.org/10.3390/toxins12110704 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30964 | |
dc.description | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. | en_US |
dc.description.abstract | Diphtheria toxin, an exotoxin secreted by Corynebacterium that causes disease in humans by inhibiting protein synthesis, enters the cell via receptor-mediated endocytosis. The subsequent endosomal acidification triggers a series of conformational changes, resulting in the refolding and membrane insertion of the translocation (T-)domain and ultimately leading to the translocation of the catalytic domain into the cytoplasm. Here, we use X-ray crystallography along with circular dichroism and fluorescence spectroscopy to gain insight into the mechanism of the early stages of pH-dependent conformational transition. For the first time, we present the high-resolution structure of the diphtheria toxin at a mildly acidic pH (5–6) and compare it to the structure at neutral pH (7). We demonstrate that neither catalytic nor receptor-binding domains change their structure upon this acidification, while the T-domain undergoes a conformational change that results in the unfolding of the TH2–3 helices. Surprisingly, the TH1 helix maintains its conformation in the crystal of the full-length toxin even at pH 5. This contrasts with the evidence from the new and previously published data, obtained by spectroscopic measurements and molecular dynamics computer simulations, which indicate the refolding of TH1 upon the acidification of the isolated T-domain. The overall results imply that the membrane interactions of the T-domain are critical in ensuring the proper conformational changes required for the preparation of the diphtheria toxin for the cellular entry. | en_US |
dc.description.sponsorship | National Institute of General Medical Sciences (P30 GM110761) | en_US |
dc.description.sponsorship | Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357 | en_US |
dc.publisher | MDPI | en_US |
dc.rights | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Diphtheria toxin structure | en_US |
dc.subject | X-ray crystallography | en_US |
dc.subject | Helix unfolding | en_US |
dc.subject | Acidification | en_US |
dc.subject | Conformational switching | en_US |
dc.title | Structure of the Diphtheria Toxin at Acidic pH: Implications for the Conformational Switching of the Translocation Domain | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Kashipathy, Maithri M. | |
kusw.kudepartment | Protein Structure Laboratory | en_US |
kusw.oanotes | Per Sherpa Romeo 12/14/2020:Toxins
[Open panel below]Publication Information
TitleToxins [English]
ISSNsElectronic: 2072-6651
URLhttp://www.mdpi.com/journal/toxins
PublishersMDPI [Commercial Publisher]
DOAJ Listinghttps://doaj.org/toc/2072-6651
Requires APCYes [Data provided by DOAJ]
[Open panel below]Publisher Policy
Open Access pathways permitted by this journal's policy are listed below by article version. Click on a pathway for a more detailed view.Published Version
NoneCC BYPMC
Any Repository, Journal Website, +1
OA PublishingThis pathway includes Open Access publishing
EmbargoNo Embargo
LicenceCC BY 4.0
Copyright OwnerAuthors
Publisher DepositPubMed Central
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Any Repository
Named Repository (PubMed Central)
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ConditionsPublished source must be acknowledged with citation
NotesAuthors are encouraged to submit their published articles to institutional repositories | en_US |
dc.identifier.doi | 10.3390/toxins12110704 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-6223-0990 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7695028 | en_US |
dc.rights.accessrights | openAccess | en_US |