This Article Full Text Full Text (PDF) Supplemental All Versions of this Article: biophysj.105.079376v1 90/9/3267    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gao, M. Articles by Schulten, K. Search for Related Content PubMed PubMed Citation Articles by Gao, M. Articles by Schulten, K.

Onset of Anthrax Toxin Pore Formation

Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Correspondence: Address reprint requests to Klaus Schulten, Tel.: 217-244-1604; Fax: 217-244-6078; E-mail: kschulte{at}ks.uiuc.edu.

Protective antigen (PA) is the anthrax toxin protein recognized by capillary morphogenesis gene 2 (CMG2), a transmembrane cellular receptor. Upon activation, seven ligand-receptor units self-assemble into a heptameric ring-like complex that becomes endocytozed by the host cell. A critical step in the subsequent intoxication process is the formation and insertion of a pore into the endosome membrane by PA. The pore conversion requires a change in binding between PA and its receptor in the acidified endosome environment. Molecular dynamics simulations totaling 136 ns on systems of over 92,000 atoms were performed. The simulations revealed how the PA-CMG2 complex, stable at neutral conditions, becomes transformed at low pH upon protonation of His-121 and Glu-122, two conserved amino acids of the receptor. The protonation disrupts a salt bridge important for the binding stability and leads to the detachment of PA domain II, which weakens the stability of the PA-CMG2 complex significantly, and subsequently releases a PA segment needed for pore formation. The simulations also explain the great strength of the PA-CMG2 complex achieves through extraordinary coordination of a divalent cation.