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Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence (2008)

C. McNamara ; A. S. Zinkernagel ; P. Macheboeuf ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 319(5868): 1405-8. doi: 10.1126/science.1154470.

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Publication Date: 2008-03-08

Description: Antigenically variable M proteins are major virulence factors and immunogens of the human pathogen group A Streptococcus (GAS). Here, we report the approximately 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2288698/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2288698/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNamara, Case -- Zinkernagel, Annelies S -- Macheboeuf, Pauline -- Cunningham, Madeleine W -- Nizet, Victor -- Ghosh, Partho -- R01 AI048694/AI/NIAID NIH HHS/ -- R01 AI052453/AI/NIAID NIH HHS/ -- R01 AI052453-08/AI/NIAID NIH HHS/ -- R21 AI071167/AI/NIAID NIH HHS/ -- R21 AI071167-01A1/AI/NIAID NIH HHS/ -- T32 GM008326/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2008 Mar 7;319(5868):1405-8. doi: 10.1126/science.1154470.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18323455" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Antibodies, Bacterial/immunology ; Antigens, Bacterial/*chemistry/genetics/immunology/metabolism ; Bacterial Outer Membrane Proteins/*chemistry/genetics/immunology/metabolism ; Carrier Proteins/*chemistry/genetics/immunology/metabolism ; Circular Dichroism ; Cross Reactions ; Crystallography, X-Ray ; Dimerization ; Fibrinogen/metabolism ; Humans ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry ; Protein Conformation ; Protein Structure, Secondary ; Repetitive Sequences, Amino Acid ; Streptococcal Infections/immunology/microbiology ; Streptococcus pyogenes/*chemistry/immunology/*pathogenicity ; Virulence

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Streptococcal M1 protein constructs a pathological host fibrinogen network (2011)

P. Macheboeuf ; C. Buffalo ; C. Y. Fu ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 472(7341): 64-8. doi: 10.1038/nature09967.

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Publication Date: 2011-04-09

Description: M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic-shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen that, unlike M1 or fibrinogen alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the complex formed between streptococcal M1 and human fibrinogen. A conformationally dynamic coiled-coil dimer of M1 was found to organize four fibrinogen molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268815/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268815/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macheboeuf, Pauline -- Buffalo, Cosmo -- Fu, Chi-yu -- Zinkernagel, Annelies S -- Cole, Jason N -- Johnson, John E -- Nizet, Victor -- Ghosh, Partho -- R01 AI052453/AI/NIAID NIH HHS/ -- R01 AI052453-10/AI/NIAID NIH HHS/ -- R01 AI077780/AI/NIAID NIH HHS/ -- R01 AI077780-03/AI/NIAID NIH HHS/ -- R01 GM54076/GM/NIGMS NIH HHS/ -- R21 AI071167/AI/NIAID NIH HHS/ -- T32 GM007240/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Apr 7;472(7341):64-8. doi: 10.1038/nature09967.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21475196" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Sequence ; Bacterial Proteins/chemistry/*metabolism/ultrastructure ; Binding Sites ; Crystallography, X-Ray ; Fibrinogen/*chemistry/metabolism/ultrastructure ; Humans ; Models, Molecular ; Neutrophil Activation ; Protein Binding ; Protein Conformation ; Shock, Septic/microbiology/physiopathology ; Streptococcus pyogenes/chemistry/*pathogenicity ; Virulence ; Virulence Factors/chemistry/*metabolism

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics