a receptor-based switch that regulates anthrax toxin pore formation炭疽毒素receptor-based开关调节孔隙的形成.pdfVIP

A Receptor-based Switch that Regulates Anthrax Toxin Pore Formation 1 2,3 1 2,3 1 Rosemarie M. Pilpa , Monika Bayrhuber , John M. Marlett , Roland Riek *, John A. T. Young * 1 Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, California, United States of America, 2 Structural Biology ¨ ¨ Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America, 3 Laboratory of Physical Chemistry, ETH Zurich, Zurich, Switzerland Abstract Cellular receptors can act as molecular switches, regulating the sensitivity of microbial proteins to conformational changes that promote cellular entry. The activities of these receptor-based switches are only partially understood. In this paper, we sought to understand the mechanism that underlies the activity of the ANTXR2 anthrax toxin receptor-based switch that binds to domains 2 and 4 of the protective antigen (PA) toxin subunit. Receptor-binding restricts structural changes within the heptameric PA prepore that are required for pore conversion to an acidic endosomal compartment. The transfer cross- saturation (TCS) NMR approach was used to monitor changes in the heptameric PA-receptor contacts at different steps during prepore-to-pore conversion. These studies demonstrated that receptor contact with PA domain 2 is weakened prior to pore conversion, defining a novel intermediate in this pathway. Importantly, ANTXR2 remained bound to PA domain 4 following pore conversion, suggesting that the bound receptor might influence the