ACTIN-BASED MOTILITY OF INTRACELLULAR PATHOGENS

Following the discovery of actin-based Listeria motility in host cells by my colleague Frederick Southwick, there has been growing interest in learning how such pathogens (including Shigella, Rickettsia, and Vaccinia) usurp the cell's contractile machinery to achieve intracellular locomotion. We have demonstrated that the Listeria surface protein uses its multiple FEFPPPPTDE registers to concentratethe host protein VASP (vasodilator-stimulated phosphoprotein) in a polarized manner on the bacterial surface. VASP in turn uses its GPPPPP sequence repeats to attract the actin regulatory protein profilin. The latter then facilitates actin filament assembly. We are investigating the motility mechanisms of both Listeria and Shigella, because the latter lacks ActA and must replace the FEFPPPPTDE sequences of ActA by using another host protein. Our working hypothesis is that Listeria and Shigella are masters at mimmicking an activated membrane complex that normally directs actin-based filopod and lamellipod extension in uninfected host cells.

Model for Actin-based Motility of Listeria--- In this model, the bacterial surface protein ActA provides four oligoproline docking sites (FEFPPPPTDE or Phe-Glu-Phe-Pro-Pro-Pro-Pro-Thr-Asp-Glu) for binding of the host protein VASP (abbreviation for: vasodilator-stimulated phosphoprotein) which is itself a tetrameric protein containing 16-20 oligoproline sites (GPPPPP or Gly-Pro-Pro-Pro-Pro-Pro). The latter serve to concentrate profilin which is a key actin regulatory protein. Although the exact role of profilin in promoting actin polymerization remains to be demonstrated unambiguously, one possibility (shown here) involves profilin's ability to catalyze exchange of ATP with ADP-actin to form ATP-actin.