{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:18:55Z","timestamp":1788283135907,"version":"build-2803163510"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"13","license":[{"start":{"date-parts":[[2015,3,18]],"date-time":"2015-03-18T00:00:00Z","timestamp":1426636800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Anthrax toxin protective antigen (PA) binds cellular receptors and self-assembles into oligomeric prepores. A prepore converts to a protein translocating pore after it has been transported to an endosome where the low pH triggers formation of a membrane-spanning \u03b2-barrel channel. Formation of this channel occurs after some PA\u2013receptor contacts are broken to allow pore formation, while others are retained to preserve receptor association. The interaction between PA and anthrax toxin receptor 1 (ANTXR1) is weaker than its interaction with ANTXR2 such that the pH threshold of ANTXR1-mediated pore formation is higher by 1 pH unit. Here we examine receptor-specific differences in toxin binding and pore formation by mutating PA residue G342 that selectively abuts ANTXR2. Mutation of G342 to valine, leucine, isoleucine, or tryptophan increased the amount of PA bound to ANTXR1-expressing cells and decreased the amount of PA bound to ANTXR2-expressing cells. The more conservative G342A mutation did not affect the level of binding to ANTXR2, but ANTXR2-bound PA-G342A prepores exhibited a pH threshold higher than that of wild-type prepores. Mixtures of wild-type PA and PA-G342A were functional in toxicity assays, and the pH threshold of ANTXR2-mediated pore formation was dictated by the relative amounts of the two proteins in the hetero-oligomers. These results suggest that PA subunits within an oligomer do not have to be triggered simultaneously for a productive membrane insertion event to occur.<\/jats:p>","DOI":"10.1021\/bi5000756","type":"journal-article","created":{"date-parts":[[2014,3,18]],"date-time":"2014-03-18T11:03:04Z","timestamp":1395140584000},"page":"2166-2171","source":"Crossref","is-referenced-by-count":3,"title":["A Protective Antigen Mutation Increases the pH Threshold\nof Anthrax Toxin Receptor 2-Mediated Pore Formation"],"prefix":"10.1021","volume":"53","author":[{"given":"Melissa K.","family":"Dennis","sequence":"first","affiliation":[{"name":"University of Toronto , , , ,","place":["Toronto, Ontario, Canada, M5S 1A8"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Mogridge","sequence":"additional","affiliation":[{"name":"University of Toronto , , , ,","place":["Toronto, Ontario, Canada, M5S 1A8"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,3,18]]},"reference":[{"key":"2026090112451152400_cit1","doi-asserted-by":"crossref","first-page":"20607","DOI":"10.1016\/S0021-9258(17)32036-7","article-title":"Anthrax\nprotective antigen forms oligomers during intoxication of mammalian\ncells","volume":"269","author":"Milne","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2026090112451152400_cit2","doi-asserted-by":"crossref","first-page":"e13888","DOI":"10.1371\/journal.pone.0013888","article-title":"Anthrax\ntoxin receptor drives protective antigen oligomerization and stabilizes\nthe heptameric and octameric oligomer by a similar mechanism","volume":"5","author":"Kintzer","year":"2010","journal-title":"PLoS One"},{"key":"2026090112451152400_cit3","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1146\/annurev.biochem.75.103004.142728","article-title":"Anthrax toxin: Receptor\nbinding, internalization, pore\nformation, and translocation","volume":"76","author":"Young","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"2026090112451152400_cit4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/pro.752","article-title":"Anthrax\ntoxin protective antigen: Insights into molecular switching from prepore\nto pore","volume":"21","author":"Bann","year":"2012","journal-title":"Protein Sci."},{"key":"2026090112451152400_cit5","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1002\/pro.2052","article-title":"Ratcheting up protein translocation\nwith anthrax toxin","volume":"21","author":"Feld","year":"2012","journal-title":"Protein Sci."},{"key":"2026090112451152400_cit6","doi-asserted-by":"crossref","first-page":"7049","DOI":"10.1073\/pnas.062160399","article-title":"Mapping the lethal\nfactor and edema factor binding sites on oligomeric anthrax protective\nantigen","volume":"99","author":"Cunningham","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090112451152400_cit7","doi-asserted-by":"crossref","first-page":"7045","DOI":"10.1073\/pnas.052160199","article-title":"The lethal\nand edema factors of anthrax toxin bind only to oligomeric forms of\nthe protective antigen","volume":"99","author":"Mogridge","year":"2002","journal-title":"Proc. Natl. Acad. Sci.\nU.S.A."},{"key":"2026090112451152400_cit8","doi-asserted-by":"crossref","first-page":"e1000792","DOI":"10.1371\/journal.ppat.1000792","article-title":"Endocytosis of the anthrax toxin is mediated by clathrin,\nactin and unconventional adaptors","volume":"6","author":"Abrami","year":"2010","journal-title":"PLoS Pathog."},{"key":"2026090112451152400_cit9","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.mam.2009.06.003","article-title":"Membrane\ntranslocation by anthrax toxin","volume":"30","author":"Collier","year":"2009","journal-title":"Mol. Aspects\nMed."},{"key":"2026090112451152400_cit10","doi-asserted-by":"crossref","first-page":"7123","DOI":"10.1016\/S0021-9258(17)38364-3","article-title":"Macrophages\nare sensitive to anthrax lethal toxin through an acid-dependent process","volume":"261","author":"Friedlander","year":"1986","journal-title":"J. Biol. Chem."},{"key":"2026090112451152400_cit11","doi-asserted-by":"crossref","first-page":"3941","DOI":"10.1021\/bi972657b","article-title":"Identification of\nresidues lining the anthrax protective antigen channel","volume":"37","author":"Benson","year":"1998","journal-title":"Biochemistry"},{"key":"2026090112451152400_cit12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1021\/bi0119518","article-title":"PA63 channel of anthrax toxin: An\nextended \u03b2-barrel","volume":"41","author":"Nassi","year":"2002","journal-title":"Biochemistry"},{"key":"2026090112451152400_cit13","doi-asserted-by":"crossref","first-page":"e1002354","DOI":"10.1371\/journal.ppat.1002354","article-title":"A receptor-based\nswitch that regulates anthrax toxin pore formation","volume":"7","author":"Pilpa","year":"2011","journal-title":"PLoS Pathog."},{"key":"2026090112451152400_cit14","doi-asserted-by":"crossref","first-page":"18378","DOI":"10.1073\/pnas.1208280109","article-title":"Anthrax\ntoxin protective antigen integrates poly-\u03b3-d-glutamate\nand pH signals to sense the optimal environment for channel formation","volume":"109","author":"Kintzer","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090112451152400_cit15","doi-asserted-by":"crossref","first-page":"13147","DOI":"10.1073\/pnas.0405405101","article-title":"Structure\nof heptameric protective antigen bound to an anthrax toxin receptor:\nA role for receptor in pH-dependent pore formation","volume":"101","author":"Lacy","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090112451152400_cit16","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/nature02763","article-title":"Crystal\nstructure of a complex between anthrax toxin and its host cell receptor","volume":"430","author":"Santelli","year":"2004","journal-title":"Nature"},{"key":"2026090112451152400_cit17","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/nsmb.1442","article-title":"GroEL as a molecular\nscaffold for structural analysis of the anthrax toxin pore","volume":"15","author":"Katayama","year":"2008","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026090112451152400_cit18","doi-asserted-by":"crossref","first-page":"13278","DOI":"10.1073\/pnas.0505865102","article-title":"Receptor-specific requirements for anthrax toxin delivery\ninto cells","volume":"102","author":"Rainey","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090112451152400_cit19","doi-asserted-by":"crossref","first-page":"39417","DOI":"10.1074\/jbc.M509049200","article-title":"Whole-cell\nvoltage clamp measurements of anthrax toxin pore current","volume":"280","author":"Wolfe","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026090112451152400_cit20","doi-asserted-by":"crossref","first-page":"e329","DOI":"10.1371\/journal.pone.0000329","article-title":"Anthrax toxin receptor 2 determinants that dictate\nthe pH threshold of toxin pore formation","volume":"2","author":"Scobie","year":"2007","journal-title":"PLoS\nOne"},{"key":"2026090112451152400_cit21","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1111\/j.1462-5822.2006.00845.x","article-title":"Characterization\nof the interaction\nbetween anthrax toxin and its cellular receptors","volume":"9","author":"Liu","year":"2007","journal-title":"Cell. Microbiol."},{"key":"2026090112451152400_cit22","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/n35101999","article-title":"Identification\nof the cellular receptor for anthrax toxin","volume":"414","author":"Bradley","year":"2001","journal-title":"Nature"},{"key":"2026090112451152400_cit23","doi-asserted-by":"crossref","first-page":"5170","DOI":"10.1073\/pnas.0431098100","article-title":"Human capillary\nmorphogenesis protein 2 functions as an anthrax toxin receptor","volume":"100","author":"Scobie","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090112451152400_cit24","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1073\/pnas.0401506101","article-title":"Crystal\nstructure of the von Willebrand factor A domain of human capillary\nmorphogenesis protein 2: An anthrax toxin receptor","volume":"101","author":"Lacy","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090112451152400_cit25","doi-asserted-by":"crossref","first-page":"e11203","DOI":"10.1371\/journal.pone.0011203","article-title":"The structure of tumor endothelial marker 8 (TEM8) extracellular\ndomain and implications for its receptor function for recognizing\nanthrax toxin","volume":"5","author":"Fu","year":"2010","journal-title":"PLoS One"},{"key":"2026090112451152400_cit26","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1146\/annurev.biophys.31.101101.140922","article-title":"Conformational regulation of integrin\nstructure and function","volume":"31","author":"Shimaoka","year":"2002","journal-title":"Annu. Rev. Biophys.\nBiomol. Struct."},{"key":"2026090112451152400_cit27","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.jmb.2004.09.067","article-title":"Acid-induced unfolding of the amino-terminal domains\nof the lethal and edema factors of anthrax toxin","volume":"344","author":"Krantz","year":"2004","journal-title":"J. Mol. Biol."},{"key":"2026090112451152400_cit28","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.jmb.2005.11.030","article-title":"Protein translocation through the\nanthrax toxin transmembrane pore is driven by a proton gradient","volume":"355","author":"Krantz","year":"2006","journal-title":"J. Mol. Biol."},{"key":"2026090112451152400_cit29","doi-asserted-by":"crossref","first-page":"23189","DOI":"10.1074\/jbc.M111.231167","article-title":"Charge requirements for proton gradient-driven\ntranslocation of anthrax toxin","volume":"286","author":"Brown","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2026090112451152400_cit30","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jmb.2006.04.072","article-title":"Self-association\nof the Transmembrane Domain of an\nAnthrax Toxin Receptor","volume":"360","author":"Go","year":"2006","journal-title":"J. Mol. Biol."},{"key":"2026090112451152400_cit31","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1157535","article-title":"The Rag GTPases\nbind raptor and mediate amino acid signaling to mTORC1","volume":"320","author":"Sancak","year":"2008","journal-title":"Science"},{"key":"2026090112451152400_cit32","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1128\/IAI.01073-08","article-title":"The cytoplasmic domain of anthrax\ntoxin receptor 1 affects binding of the protective antigen","volume":"77","author":"Go","year":"2009","journal-title":"Infect. Immun."},{"key":"2026090112451152400_cit33","doi-asserted-by":"crossref","first-page":"15737","DOI":"10.1021\/bi981436i","article-title":"Characterization\nof membrane translocation by anthrax protective antigen","volume":"37","author":"Wesche","year":"1998","journal-title":"Biochemistry"},{"key":"2026090112451152400_cit34","doi-asserted-by":"crossref","first-page":"10432","DOI":"10.1021\/bi990792d","article-title":"Anthrax protective antigen: Prepore-to-pore\nconversion","volume":"38","author":"Miller","year":"1999","journal-title":"Biochemistry"}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi5000756","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/13\/2166\/7889327\/bi5000756.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/13\/2166\/7889327\/bi5000756.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:45:22Z","timestamp":1788281122000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/53\/13\/2166\/774155\/A-Protective-Antigen-Mutation-Increases-the-pH"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,18]]},"references-count":34,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2014,3,18]]},"published-print":{"date-parts":[[2014,4,8]]}},"URL":"https:\/\/doi.org\/10.1021\/bi5000756","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,18]]}}}