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Science 7 March 2008:
Vol. 319. no. 5868, pp. 1405 - 1408
DOI: 10.1126/science.1154470
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Reports

Coiled-Coil Irregularities and Instabilities in Group A Streptococcus M1 Are Required for Virulence

Case McNamara,1* Annelies S. Zinkernagel,2 Pauline Macheboeuf,1 Madeleine W. Cunningham,3 Victor Nizet,2,4 Partho Ghosh1,5{dagger}

Antigenically variable M proteins are major virulence factors and immunogens of the human pathogen group A Streptococcus (GAS). Here, we report the ~3 angstrom resolution structure of a GAS M1 fragment containing the regions responsible for eliciting type-specific, protective immunity and for binding fibrinogen, which promotes M1 proinflammatory and antiphagocytic functions. The structure revealed substantial irregularities and instabilities throughout the coiled coil of the M1 fragment. Similar structural irregularities occur in myosin and tropomyosin, explaining the patterns of cross-reactivity seen in autoimmune sequelae of GAS infection. Sequence idealization of a large segment of the M1 coiled coil enhanced stability but diminished fibrinogen binding, proinflammatory effects, and antibody cross-reactivity, whereas it left protective immunogenicity undiminished. Idealized M proteins appear to have promise as vaccine immunogens.

1 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
2 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
3 University of Oklahoma Health Sciences Center, Biomedical Research Center, 975 North East 10th Street, Oklahoma City, OK 73104, USA.
4 School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
5 Section of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.

* Present address: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

{dagger} To whom correspondence should be addressed. E-mail: pghosh{at}ucsd.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)