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PRP as a New Approach to Prevent Infection: Preparation and In vitro Antimicrobial Properties of PRP
Published on: April 9, 2013
The plasminogen-binding group A streptococcal M protein-related protein Prp binds plasminogen via arginine and
Martina L Sanderson-Smith1, Mark Dowton, Marie Ranson
1School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
Abstract:
The migration of the human pathogen Streptococcus pyogenes (group A streptococcus) from localized to deep tissue sites may result in severe invasive disease, and sequestration of the host zymogen plasminogen appears crucial for virulence. Here, we describe a novel plasminogen-binding M protein, the plasminogen-binding group A streptococcal M protein (PAM)-related protein (Prp). Prp is phylogenetically distinct from previously described plasminogen-binding M proteins of group A, C, and G streptococci. While competition experiments indicate that Prp binds plasminogen with a lower affinity than PAM (50% effective concentration = 0.34 microM), Prp nonetheless binds plasminogen with high affinity and at physiologically relevant concentrations of plasminogen (K(d) = 7.8 nM). Site-directed mutagenesis of the putative plasminogen binding site indicates that unlike the majority of plasminogen receptors, Prp does not interact with plasminogen exclusively via lysine residues. Mutagenesis to alanine of lysine residues Lys(96) and Lys(101) reduced but did not abrogate plasminogen binding by Prp. Plasminogen binding was abolished only with the additional mutagenesis of Arg(107) and His(108) to alanine. Furthermore, mutagenesis of Arg(107) and His(108) abolished plasminogen binding by Prp despite the presence of Lys(96) and Lys(101) in the binding site. Thus, binding to plasminogen via arginine and histidine residues appears to be a conserved mechanism among plasminogen-binding M proteins.
Insights
Streptococcus pyogenes uses a novel protein, Prp, to bind host plasminogen, aiding its spread to deep tissues. This binding mechanism involves arginine and histidine residues, differing from other known plasminogen-binding proteins.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Streptococcus pyogenes (group A Streptococcus) causes invasive disease by migrating to deep tissues.
- Plasminogen sequestration by the pathogen is critical for its virulence.
- Existing plasminogen-binding M proteins from various streptococci have known binding mechanisms.
Purpose of the Study:
- To characterize a novel plasminogen-binding M protein, Prp, from Streptococcus pyogenes.
- To determine the phylogenetic distinctiveness of Prp compared to other plasminogen-binding M proteins.
- To elucidate the specific residues and mechanism involved in Prp's plasminogen binding.
Main Methods:
- Phylogenetic analysis to compare Prp with known M proteins.
- Plasminogen binding assays, including competition experiments and determination of binding affinity (Kd).
- Site-directed mutagenesis of Prp to identify key residues in plasminogen binding.
Main Results:
- Prp is a novel, phylogenetically distinct plasminogen-binding M protein.
- Prp binds plasminogen with high affinity (Kd = 7.8 nM) at physiological concentrations.
- Unlike other receptors, Prp binding does not exclusively involve lysine residues; Arg(107) and His(108) are crucial for binding.
Conclusions:
- Prp represents a new class of plasminogen-binding M proteins in Streptococcus pyogenes.
- The binding mechanism of Prp highlights the importance of arginine and histidine residues.
- This conserved binding mechanism involving arginine and histidine may be a common strategy among plasminogen-binding M proteins.
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