Human C4b-binding Protein, Structural Basis for Interaction with Streptococcal M Protein, a Major Bacterial Virulence Factor

Huw T Jenkins,Linda Mark,Graeme Ball,Jenny Persson,Gunnar Lindahl,Dusan Uhrin,Anna M Blom,Paul N Barlow

doi:10.1074/jbc.m511563200

Huw T Jenkins, Linda Mark + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m511563200

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Abstract

Human C4b-binding protein (C4BP) protects host tissue, and those pathogens able to hijack this plasma glycoprotein, from complement-mediated destruction. We now show that the first two complement control protein (CCP) modules of the C4BP alpha-chain, plus the four residues connecting them, are necessary and sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes M4 (Arp4) protein. Structure determination by NMR reveals two tightly coupled CCP modules in an elongated arrangement within this region of C4BP. Chemical shift perturbation studies demonstrate that the N-terminal, hypervariable region of M4 binds to a site including strand 1 of CCP module 2. This interaction is accompanied by an intermodular reorientation within C4BP. We thus provide a detailed picture of an interaction whereby a pathogen evades complement.

Highlights

Bacteria that enter human blood or tissues will be opsonized by complement and destroyed by phagocytes unless they have a means of overcoming attack by the complement system
We show that the first two complement control protein (CCP) modules of the C4bbinding protein (C4BP) ␣-chain, plus the four residues connecting them, are necessary and sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes M4 (Arp4) protein
An extensively studied example of such a virulence mechanism is the ability of many Streptococcus pyogenes M proteins to bind the key human complement regulator C4bbinding protein (C4BP),2 an interaction that endows the bacteria with resistance to phagocytosis [1]

Summary

Introduction

Bacteria that enter human blood or tissues will be opsonized by complement and destroyed by phagocytes unless they have a means of overcoming attack by the complement system. We show that the first two complement control protein (CCP) modules of the C4BP ␣-chain, plus the four residues connecting them, are necessary and sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes M4 (Arp4) protein.

Results

Conclusion