Solution structural model of the complex of the binding regions of human plasminogen with its M-protein receptor from Streptococcus pyogenes

The M protein of Streptococcus pyogenes is a major bacterial virulence factor that confers resistance to phagocytosis. To analyze how M protein allows evasion of phagocytosis, we used the M22 protein, which has features typical of many M proteins and has two well-characterized regions binding human plasma proteins: the hypervariable NH2-terminal region binds C4b-binding protein (C4BP), which inhibits the classical pathway of complement activation; and an adjacent semivariable region binds IgA-Fc. Characterization of chromosomal S. pyogenes mutants demonstrated that each of the ligand-binding regions contributed to phagocytosis resistance, which could be fully explained as cooperation between the two regions. Deposition of complement on S. pyogenes occurred almost exclusively via the classical pathway, even under nonimmune conditions, but was down-regulated by bacteria-bound C4BP, providing an explanation for the ability of bound C4BP to inhibit phagocytosis. Different opsonizing antisera shared the ability to block binding of both C4BP and IgA, suggesting that the two regions in M22 play important roles also under immune conditions, as targets for protective antibodies. These data indicate that M22 and similar M proteins confer resistance to phagocytosis through ability to bind two components of the human immune system.

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Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen Binding

Journal of Molecular Biology ◽

10.1016/j.jmb.2019.07.003 ◽

2019 ◽

Vol 431 (19) ◽

pp. 3804-3813 ◽

Cited By ~ 1

Author(s):

Adam J.H. Quek ◽

Blake A. Mazzitelli ◽

Guojie Wu ◽

Eleanor W.W. Leung ◽

Tom T. Caradoc-Davies ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Structure And Function ◽

M Protein ◽

Function Characterization ◽

Human Plasminogen ◽

And Function

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Protein F1 and Streptococcus pyogenes Resistance to Phagocytosis

Infection and Immunity ◽

10.1128/iai.01745-06 ◽

2007 ◽

Vol 75 (6) ◽

pp. 3188-3191 ◽

Cited By ~ 14

Author(s):

Kendra A. Hyland ◽

Beinan Wang ◽

P. Patrick Cleary

Keyword(s):

Epithelial Cells ◽

Protein Expression ◽

Streptococcus Pyogenes ◽

Binding Proteins ◽

M Protein ◽

Partial Inhibition ◽

Fibronectin Binding ◽

Negative Mutant

ABSTRACT Streptococcus pyogenes is a major cause of pharyngitis in humans and encodes several fibronectin-binding proteins. M protein and protein F1 (PrtF1/SfbI) are differentially regulated by CO2 and O2, respectively, and both mediate the invasion of epithelial cells. This study examined whether PrtF1/SfbI shares other properties with M protein. Expression of the PrtF1/SfbI protein by an M-negative mutant conferred resistance to phagocytosis and partial inhibition of C3 deposition on the S. pyogenes surface.

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Identification of a divergent M protein gene and an M protein-related gene family in Streptococcus pyogenes serotype 49.

Journal of Bacteriology ◽

10.1128/jb.171.12.6397-6408.1989 ◽

1989 ◽

Vol 171 (12) ◽

pp. 6397-6408 ◽

Cited By ~ 63

Author(s):

E J Haanes ◽

P P Cleary

Keyword(s):

Gene Family ◽

Streptococcus Pyogenes ◽

Protein Gene ◽

M Protein ◽

Related Gene

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Formation of Molecular Complexes Between a Structurally Defined M Protein and Acylated or Deacylated Lipoteichoic Acid of Streptococcus pyogenes

Journal of Bacteriology ◽

10.1128/jb.149.2.426-433.1982 ◽

1982 ◽

Vol 149 (2) ◽

pp. 426-433 ◽

Cited By ~ 56

Author(s):

Itzhak Ofek ◽

W. Andrew Simpson ◽

Edwin H. Beachey

Keyword(s):

Streptococcus Pyogenes ◽

Molecular Complexes ◽

Lipoteichoic Acid ◽

M Protein

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Host Pathways of Hemostasis that Regulate Group A Streptococcus pyogenes Pathogenicity

Current Drug Targets ◽

10.2174/1389450120666190926152914 ◽

2020 ◽

Vol 21 (2) ◽

pp. 193-201

Author(s):

Victoria A. Ploplis ◽

Francis J. Castellino

Keyword(s):

Streptococcus Pyogenes ◽

Inflammatory Responses ◽

Group A Streptococcus ◽

Protein A ◽

M Protein ◽

Severe Group ◽

Group A ◽

Flow Through ◽

Hallmark Feature ◽

Major Target

A hallmark feature of severe Group A Streptococcus pyogenes (GAS) infection is dysregulated hemostasis. Hemostasis is the primary pathway for regulating blood flow through events that contribute towards clot formation and its dissolution. However, a number of studies have identified components of hemostasis in regulating survival and dissemination of GAS. Several proteins have been identified on the surface of GAS and they serve to either facilitate invasion to host distal sites or regulate inflammatory responses to the pathogen. GAS M-protein, a surface-exposed virulence factor, appears to be a major target for interactions with host hemostasis proteins. These interactions mediate biochemical events both on the surface of GAS and in the solution when M-protein is released into the surrounding environment through shedding or regulated proteolytic processes that dictate the fate of this pathogen. A thorough understanding of the mechanisms associated with these interactions could lead to novel approaches for altering the course of GAS pathogenicity.

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