{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:07:57Z","timestamp":1790698077051,"version":"4.1.0"},"reference-count":58,"publisher":"American Chemical Society (ACS)","issue":"38","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr?d","doi-asserted-by":"publisher","award":["262695"],"award-info":[{"award-number":["262695"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI137056"],"award-info":[{"award-number":["R01AI137056"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sigma2 - the National infrastructure for high-performance computing and data storage in Norway","award":["NN4654K"],"award-info":[{"award-number":["NN4654K"]}]},{"name":"Sigma2 - the National infrastructure for high-performance computing and data storage in Norway","award":["NS4654K"],"award-info":[{"award-number":["NS4654K"]}]},{"name":"Norwegian Macromolecular Crystallography Consortium and Norwegian INFRASTRUKTUR-program","award":["245828"],"award-info":[{"award-number":["245828"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cholera toxin (CT) from Vibrio cholerae and heat-labile enterotoxin (LT) from enterotoxigenic Escherichia coli are highly related AB5-type protein toxins that contain a catalytic A1 subunit, an A2 linker, and a cell-binding homopentamer of B subunits. The two proteins bind the same GM1 receptor and have similar levels of enzymatic activity toward their shared Gs\u03b1 target, yet CT is more potent than LT. This difference has been mapped to a sequence of 11 amino acids (residues 226\u2013236) near the C-terminus of the A2 linker. We now identify a single amino acid, aspartic acid at position 229, as a key contributor to the function of CT: substituting it for glutamic acid 229 from LT reduced the toxicity of CT to the level of LT. Toxin disassembly by protein disulfide isomerase (PDI), which is an essential event in the intoxication process, was less efficient for CTD229E and LT than for wild-type CT. This was further confirmed by a CT variant, in which four residues were converted into the LT sequence (D229E, I230V, T232I, and H233Y). To test our previous hypothesis that the positioning of the A1 subunit over the B pentamer critically determines toxin disassembly and thus potency, we determined crystal structures of both toxin variants to 1.6 \u00c5 resolution and calculated the angle at which the A2 linker exits the pore. The conformations of the two toxin chimeras lie between CT and LT, with the A2 C-terminus of the CT quadruple variant adopting essentially the same fold as LT. The A subunits of the toxin variants as well as that of LT showed a higher conformational freedom than CT as determined by molecular dynamics simulations, suggesting that a more rigid positioning of the A subunit drives toxin disassembly and potency. Our collective data uncover the critical role of D229 in toxin folding and structural dynamics, which in turn impacts toxin potency through effects on the efficiency of PDI-driven toxin disassembly.<\/jats:p>","DOI":"10.1021\/acsomega.6c07022","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:02:11Z","timestamp":1789603331000},"page":"57763-57780","source":"Crossref","is-referenced-by-count":0,"title":["A Single Amino\nAcid in the A2 Linker of Cholera Toxin\nAffects the Efficiency of Toxin Disassembly and Resulting Toxicity"],"prefix":"10.1021","volume":"11","author":[{"given":"Flore","family":"Kersten","sequence":"first","affiliation":[{"name":"University of Oslo , , ,","place":["Oslo, Norway, NO-0318"]},{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Mojica","sequence":"additional","affiliation":[{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]},{"name":"University of Oslo , , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Serrano","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9702-9480","authenticated-orcid":true,"given":"Joel B.","family":"Heim","sequence":"additional","affiliation":[{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Guyette","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7553-0482","authenticated-orcid":true,"given":"Henrique Musseli","family":"Cezar","sequence":"additional","affiliation":[{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]},{"name":"University of Oslo , , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8029-8043","authenticated-orcid":true,"given":"Gabriele","family":"Cordara","sequence":"additional","affiliation":[{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]},{"name":"University of Oslo , , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suren A.","family":"Tatulian","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2266-5399","authenticated-orcid":true,"given":"Michele","family":"Cascella","sequence":"additional","affiliation":[{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]},{"name":"University of Oslo , , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-8151","authenticated-orcid":true,"given":"Ute","family":"Krengel","sequence":"additional","affiliation":[{"name":"University of Oslo , , Blindern , ,","place":["Oslo, Norway, NO-0371"]},{"name":"University of Oslo , , ,","place":["Oslo, Norway, NO-0371"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4176-9361","authenticated-orcid":true,"given":"Ken","family":"Teter","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32816"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"issue":"10101","key":"2026092911125213100_cit1","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1016\/S0140-6736(17)30559-7","article-title":"Cholera","volume":"390","author":"Clemens","year":"2017","journal-title":"Lancet"},{"issue":"8","key":"2026092911125213100_cit2","doi-asserted-by":"publisher","first-page":"2132","DOI":"10.3390\/toxins2082132","article-title":"Toxin mediated diarrhea in the 21st century:\nthe pathophysiology of intestinal ion transport in the course of ETEC, V. cholerae and rotavirus infection","volume":"2","author":"Kopic","year":"2010","journal-title":"Toxins"},{"issue":"4","key":"2026092911125213100_cit3","first-page":"370","article-title":"Prevalence of enterotoxigenic Escherichia coli-associated diarrhoea and carrier state in the developing world","volume":"22","author":"Wennera\u030as","year":"2004","journal-title":"J. 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Chem."},{"issue":"11","key":"2026092911125213100_cit9","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00332-23","article-title":"Reduction\nis sufficient for the disassembly\nof ricin and Shiga toxin 1 but not Escherichia coli heat-labile enterotoxin","volume":"91","author":"Guyette","year":"2023","journal-title":"Infect. 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Rep."},{"issue":"13","key":"2026092911125213100_cit17","doi-asserted-by":"publisher","first-page":"3772","DOI":"10.1021\/bi0360152","article-title":"Crystal\nstructures of an intrinsically active cholera toxin mutant yield insight\ninto the toxin activation mechanism","volume":"43","author":"O\u2019Neal","year":"2004","journal-title":"Biochemistry"},{"issue":"3","key":"2026092911125213100_cit18","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1006\/jmbi.1993.1209","article-title":"Refined\nstructure of Escherichia coli heat-labile enterotoxin, a close relative of cholera\ntoxin","volume":"230","author":"Sixma","year":"1993","journal-title":"J. Mol. 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Biol."},{"issue":"6","key":"2026092911125213100_cit24","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1107\/s0909049509036681","article-title":"EDNA: a framework\nfor plugin-based\napplications applied to X-ray experiment online data analysis","volume":"16","author":"Incardona","year":"2009","journal-title":"J. Synchrotron Rad."},{"issue":"3","key":"2026092911125213100_cit25","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1107\/S0021889812011715","article-title":"XDSAPP: a graphical user interface\nfor the convenient processing of diffraction\ndata using XDS","volume":"45","author":"Krug","year":"2012","journal-title":"J. Appl. Crystallogr."},{"key":"2026092911125213100_cit100","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic\nsoftware","volume":"40","author":"McCoy","year":"2007","journal-title":"J. Appl. Crystallogr."},{"issue":"4","key":"2026092911125213100_cit26","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1002\/pro.3791","article-title":"Current developments\nin Coot for macromolecular model building of electron\ncryo-microscopy and\ncrystallographic data","volume":"29","author":"Casan\u0303al","year":"2020","journal-title":"Protein Sci."},{"issue":"4","key":"2026092911125213100_cit27","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development\nof Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr.\nD Biol. Crystallogr."},{"issue":"4","key":"2026092911125213100_cit28","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1107\/S0907444911001314","article-title":"REFMAC5 for the refinement of macromolecular\ncrystal structures","volume":"67","author":"Murshudov","year":"2011","journal-title":"Acta Crystallogr. D Biol.\nCrystallogr."},{"issue":"4","key":"2026092911125213100_cit29","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1107\/S0907444912001308","article-title":"Towards\nautomated crystallographic\nstructure refinement with phenix.refine","volume":"68","author":"Afonine","year":"2012","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"issue":"1","key":"2026092911125213100_cit30","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic\nAcids Res."},{"issue":"4","key":"2026092911125213100_cit31","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1006\/jmbi.1995.0456","article-title":"The three-dimensional\ncrystal structure\nof cholera toxin","volume":"251","author":"Zhang","year":"1995","journal-title":"J. Mol. 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Biol.\nChem."},{"issue":"7","key":"2026092911125213100_cit39","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/bioinformatics\/btt055","article-title":"GROMACS 4.5: a high-throughput\nand highly parallel open source molecular simulation toolkit","volume":"29","author":"Pronk","year":"2013","journal-title":"Bioinformatics"},{"key":"2026092911125213100_cit40","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance\nmolecular simulations through multi-level parallelism from laptops\nto supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"issue":"8","key":"2026092911125213100_cit41","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain\ntorsion potentials for the Amber ff99SB protein force field","volume":"78","author":"Lindorff-Larsen","year":"2010","journal-title":"Proteins"},{"issue":"2","key":"2026092911125213100_cit42","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison\nof simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. 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Struct.\nDyn."},{"issue":"7","key":"2026092911125213100_cit49","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1002\/bip.1967.360050708","article-title":"General method for\ncalculating helical parameters of\npolymer chains from bond lengths, bond angles, and internal-rotation\nangles","volume":"5","author":"Sugeta","year":"1967","journal-title":"Biopolymers"},{"issue":"3","key":"2026092911125213100_cit50","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1021\/jp506509c","article-title":"Biophysical\ncharacteristics of cholera toxin and Escherichia coli heat-labile enterotoxin structure and chemistry lead to differential\ntoxicity","volume":"119","author":"Craft","year":"2015","journal-title":"J. Phys. Chem. B"},{"issue":"11","key":"2026092911125213100_cit52","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1016\/S0969-2126(97)00298-0","article-title":"Structural foundation\nfor the design of receptor antagonists targeting Escherichia coli heat-labile enterotoxin","volume":"5","author":"Merritt","year":"1997","journal-title":"Structure"},{"issue":"2","key":"2026092911125213100_cit53","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1107\/S0907444900016814","article-title":"Exploration\nof the GM1 receptor-binding site of heat-labile\nenterotoxin and cholera toxin by phenyl-ring-containing galactose\nderivatives","volume":"57","author":"Fan","year":"2001","journal-title":"Acta Crystallogr., Sect. 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