The structure, dynamics and function of the pore-forming toxin of Anthrax

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DESCRIPTION (provided by applicant): Protective Antigen (PA) is the receptor-binding component of the anthrax toxin that plays a pivotal role in the translocation of the anthrax enzymatic components, Lethal Factor (LF) and Edema Factor (EF) into host cells. PA forms a non-constitutive b-barrel pore in endosomal membranes by a process that involves its intermolecular interactions with its receptor (ANTXR1 or ANTXR2) at acidic pH. Our main objective of this grant application is to understand the poorly defined structural and dynamic interactions between PA and its target receptor that lead to pore formation. To accomplish these goals, we intend to study the membrane inserted pore and the interaction of PA with its receptor at atomic resolution using a combination of nuclear magnetic resonance (NMR) and biochemical techniques. Using these procedures, we will (1) solve the high- resolution structure of the PA pore formed within micelles, (2) evaluate the dynamics of the heptameric PA that leads to pore formation at a range of different pH values, and (3) examine the structural and dynamic changes that govern the PA:receptor complex as it enters into a low pH environment. The results of our investigation will provide the basis for understanding the structural rearrangements of the PA:receptor complex that lead to pore formation, and give insights into the translocation process with the atomic details of the heptameric pore. Results of these studies will be the foundation for the rational basis for designing novel therapeutics to block anthrax toxin pore formation and translocation into cells.