Title : Binding and activation of fibrinolytic components to group A streptococcus pyogenes enhances microbial pathogenicity

Abstract:

Binding and activation of components of the human fibrinolytic system enhances the pathogenicity of Streptococcus pyogenes (GAS) by allowing a potent serine protease, human plasmin (hPm) to be present on the surface of these cells. The major receptors of hPg and hPm on these cells are streptococcal M-protein (PAM) of Pattern D strains of GAS, as well as streptococcal enolase (SEn). We have studied the binding of intact hPg to these proteins at high resolution using cryogenic electron microscopy (cryoEM) and have obtained resolutions <3.6Å, thus allowing the mechanisms of binding to be determined. These studies were combined with activation analyses of hPg by GAS-secreted streptokinase (SK) to correlate plasminogen binding, activation and pathogenicity. We find that only Pattern D strains of GAS directly bind hPg and hPm via a short region of the hPg, termed kringle 2, and the a-domain of PAM. Binding to SEn is more complex with several hPg kringles interaction with an internal lysine isostere of SEn. However, the complex of Sen and hPg does not result in its enhanced activation by SK, but this binding does promote slightly enhanced activation of hPg by host tissue-type plasminogen activator. We conclude that the pathogenicity of Pattern D GAS is primarily accomplished by hPg binding to PAM.

Biography:

Professor Francis J. Castellino obtained his B.S in Chemistry from the University of Scranton, his M.S. and Ph.D. degrees in Biochemistry from the University of Iowa and was a postdoctoral fellow at Duke University. He currently is the Kleiderer/Pezold Professor of Biochemistry and Director of the WM Keck Center for Transgene Research, University of Notre Dame.  The research interests of Prof. Castellino’s laboratory involve the in vitro, in vivo, and ex vivo structure, function, and activation of components of blood coagulation and blood clot dissolution and their relationships to inflammatory and infectious disease.  He, as an author and co-author of more than 500 articles in scholarly journals, which have around 21,000 citations.