Streptococcal M protein:: Structural studies of the hypervariable region, free and bound to human C4BP
Streptococcal M protein:: Structural studies of the hypervariable region, free and bound to human C4BP
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DOI：
10.1021/bi052455c
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发表时间：
2006-04-11
期刊：
影响因子：
2.9
通讯作者：
Linse, S
中科院分区：
文献类型：
--
作者：
André, I;Persson, J;Linse, S
化脓性链球菌是一种革兰氏阳性菌，可引起多种疾病，包括急性扁桃体炎和中毒性休克综合征。定位于表面的M蛋白是研究最广泛的S.化脓性链球菌具有类似于50个残基的N-末端高变区（HVR），其在宿主免疫逃逸中起关键作用。尽管该区域存在广泛的序列变异性，但许多HVR特异性结合人C4b结合蛋白（C4BP），这是一种抑制补体激活的血浆蛋白。虽然已知M蛋白的更保守部分具有二聚卷曲螺旋结构，但尚不清楚HVR是否也是卷曲螺旋。在这里，我们使用核磁共振（NMR）研究的构象特性的HVR从M4和M22蛋白的分离和复杂的M蛋白结合部分的C4BP。我们得出结论，M4和M22的HVR折叠为卷曲螺旋，并且M4 HVR的折叠核具有类似于27个残基的长度。此外，我们证明了M4-N的C4BP结合表面被发现在四个七肽重复的区域内。使用分子建模，我们提出了一个模型的M4 HVR的结构，这是与我们的实验信息从NMR光谱。
Streptococcus pyogenes is a Gram-positive bacterium that causes several diseases, including acute tonsillitis and toxic shock syndrome. The surface-localized M protein, which is the most extensively studied virulence factor of S. pyogenes, has an similar to 50-residue N-terminal hypervariable region (HVR) that plays a key role in the escape of the host immunity. Despite the extensive sequence variability in this region, many HVRs specifically bind human C4b-binding protein (C4BP), a plasma protein that inhibits complement activation. Although the more conserved parts of M protein are known to have dimeric coiled-coil structure, it is unclear whether the HVR also is a coiled coil. Here, we use nuclear magnetic resonance (NMR) to study the conformational properties of HVRs from M4 and M22 proteins in isolation and in complex with the M protein binding portion of C4BP. We conclude that the HVRs of M4 and M22 are folded as coiled coils and that the folded nucleus of the M4 HVR has a length of similar to 27 residues. Moreover, we demonstrate that the C4BP binding surface of M4-N is found within a region of four heptad repeats. Using molecular modeling, we propose a model for the structure of the M4 HVR that is consistent with our experimental information from NMR spectroscopy.