McNamara Case, Zinkernagel Annelies S, Macheboeuf Pauline, Cunningham Madeleine W, Nizet Victor, Ghosh Partho
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Science. 2008 Mar 7;319(5868):1405-8. doi: 10.1126/science.1154470.
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.
抗原可变的M蛋白是人类病原体A组链球菌（GAS）的主要毒力因子和免疫原。在此，我们报告了一个GAS M1片段的约3埃分辨率结构，该片段包含引发型特异性保护性免疫以及结合纤维蛋白原的区域，纤维蛋白原可促进M1的促炎和抗吞噬功能。该结构显示M1片段的卷曲螺旋结构整体存在大量不规则性和不稳定性。肌球蛋白和原肌球蛋白中也存在类似的结构不规则性，这解释了GAS感染自身免疫后遗症中所见的交叉反应模式。M1卷曲螺旋的一大段序列理想化增强了稳定性，但降低了纤维蛋白原结合能力、促炎作用和抗体交叉反应性，而保护性免疫原性未受影响。理想化的M蛋白似乎有望作为疫苗免疫原。
