Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.
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.
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Cosmo Z
CZ
Buffalo
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Adrian J
AJ
Bahn-Suh
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Sophia P
SP
Hirakis
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Tapan
T
Biswas
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Rommie E
RE
Amaro
Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.|Skaggs School of Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.
Victor
V
Nizet
Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Partho
P
Ghosh
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000737:chemistry* / Q000378:metabolism; D003169:Complement Inactivator Proteins; D017124:Conserved Sequence; D054884:Host-Pathogen Interactions; D006801:Humans
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; C055609:C4BPA protein, human; D002352:Carrier Proteins; D050716:Complement C4b-Binding Protein; D003169:Complement Inactivator Proteins; C014689:streptococcal M protein