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Nat Microbiol. 2016 Sep 5;1(11):16155. doi: 10.1038/nmicrobiol.2016.155.

Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.

Author information

1
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
2
Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.
3
Skaggs School of Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.

Abstract

No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M protein HVRs (apparently ∼90%). Such broad recognition is rare, and we discovered a unique mechanism for this through the structure determination of four sequence-diverse M proteins in complexes with C4BP. The structures revealed a uniform and tolerant 'reading head' in C4BP, which detected conserved sequence patterns hidden within hypervariability. Our results open up possibilities for rational therapies that target the M-C4BP interaction, and also inform a path towards vaccine design.

Comment in

PMID:
27595425
PMCID:
PMC5014329
DOI:
10.1038/nmicrobiol.2016.155
[Indexed for MEDLINE]
Free PMC Article

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