{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:38:55Z","timestamp":1790919535689,"version":"4.1.0"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,11,6]]},"abstract":"<jats:p>\n                    Many toxins assemble into oligomers on the surface of cells. Local chemical cues signal and trigger critical rearrangements of the oligomer, inducing the formation of a membrane-fused or channel state.\n                    <jats:italic>Bacillus anthracis<\/jats:italic>\n                    secretes two virulence factors: a tripartite toxin and a poly-\u03b3-\n                    <jats:sc>d<\/jats:sc>\n                    -glutamic acid capsule (\u03b3-DPGA). The toxin\u2019s channel-forming component, protective antigen (PA), oligomerizes to create a prechannel that forms toxic complexes upon binding the two other enzyme components, lethal factor (LF) and edema factor (EF). Following endocytosis into host cells, acidic pH signals the prechannel to form the channel state, which translocates LF and EF into the host cytosol. We report \u03b3-DPGA binds to PA, LF, and EF, exhibiting nanomolar avidity for the PA prechannel oligomer. We show PA channel formation requires the pH-dependent disruption of the intra-PA domain-2\u2013domain-4 (D2-D4) interface. \u03b3-DPGA stabilizes the D2-D4 interface, preventing channel formation both in model membranes and cultured mammalian cells. A 1.9-\u00c5 resolution X-ray crystal structure of a D2-D4-interface mutant and corresponding functional studies reveal how stability at the intra-PA interface governs channel formation. We also pinpoint the kinetic pH trigger for channel formation to a residue within PA\u2019s membrane-insertion loop at the inter-PA D2-D4 interface. Thus, \u03b3-DPGA may function as a chemical cue, signaling that the local environment is appropriate for toxin assembly but inappropriate for channel formation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1208280109","type":"journal-article","created":{"date-parts":[[2012,10,25]],"date-time":"2012-10-25T20:21:47Z","timestamp":1351196507000},"page":"18378-18383","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Anthrax toxin protective antigen integrates poly-\u03b3-\n                    <scp>d<\/scp>\n                    -glutamate and pH signals to sense the optimal environment for channel formation"],"prefix":"10.1073","volume":"109","author":[{"given":"Alexander F.","family":"Kintzer","sequence":"first","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iok I","family":"Tang","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam K.","family":"Schawel","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Brown","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan A.","family":"Krantz","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"},{"name":"Molecular and Cell Biology, and"},{"name":"California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,10,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/nsmb.1923","article-title":"Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers","volume":"17","author":"Feld GK","year":"2010","unstructured":"GK Feld, et al., Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers. 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