Monitoring conformational rearrangements in Bacillus anthracis protective antigen using FRET microscopy

CHED 346

Sharline Madera, Smadera@Wellesley.edu1, Kenneth A. Christensen, kchris@clemson.edu2, and Thomas P. Caldwell2. (1) Department of Chemistry, Wellesley College, 106 Central Street, Wellesley, MA 02481, (2) Department of Chemistry, Clemson University, 118 Biosystems Research Complex, Clemson, SC 29634
Conformational rearrangements in Bacillus anthracis Protective Antigen (PA) were monitored using Fluorescence Resonance Energy Transfer (FRET) microscopy. PA oligomerizes to a PA prepore heptamer, which is taken into the cell by endocytosis. The endosomal environment triggers conformational rearrangements in PA to form a pore. One cysteine mutant per domain of PA was created by site directed mutagenesis and tagged with acceptor or donor fluorophores. Ogliomerization of PA mutant pairs was done in vitro. These resulting heptamers were then incubated in CHO-ATR-1 cells and FRET Efficiency was monitored for the PA prepore and PA pore conformations. Through obtained FRET efficiencies we have estimated relative conformational rearrangements between domains of PA prepore to PA pore. Comparison of our FRET data to a recently proposed model of PA pore, based primarily on PA homology with Staphylococcus aureus á-hemolysin, showed significant deviations from this model and will provide a basis for new structural models.