Structure of the Hemoglobin-IsdH Complex Reveals the Molecular Basis of Iron Capture by Staphylococcus aureus
Structure of the Hemoglobin-IsdH Complex Reveals the Molecular Basis of Iron Capture by Staphylococcus aureus
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DOI：
10.1074/jbc.m113.545566
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发表时间：
2014-03-07
影响因子：
4.8
通讯作者：
Gell, David A.
中科院分区：
文献类型：
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作者：
Dickson, Claire F.;Kumar, Kaavya Krishna;Gell, David A.
背景：金黄色葡萄球菌的 IsdB 和 IsdH 蛋白从人血红蛋白中剥离血红素铁。结果：IsdH 血红蛋白复合物显示 IsdH 的球蛋白结合和血红素结合 NEAT 结构域如何协作从血红蛋白两条链中去除血红素。结论：IsdH 的超域结构通过精确定位血红素受体域来赋予活性。意义：多个 Isd 血红蛋白界面可能成为新抗生素的靶点。金黄色葡萄球菌会导致人类罹患危及生命的疾病。金黄色葡萄球菌表面蛋白铁调节表面决定簇 H (IsdH) 与哺乳动物血红蛋白 (Hb) 结合，并提取血红素作为铁的来源，而铁是细菌的必需营养素。然而，人们对血红素从 Hb 转移的过程知之甚少。我们通过 X 射线晶体学以 4.2 分辨率确定了与人 Hb 结合的 IsdH 的结构，揭示了血红素转移的结构基础。一个 IsdH 分子与每个 Hb 亚基结合，表明受体通过类似的机制从两条链获取铁。值得注意的是，IsdH 中的两个近铁转运蛋白 (NEAT) 结构域执行着截然不同的功能。 N 端 NEAT 结构域通过远离球蛋白血红素袋的位点结合/球蛋白，并通过介入结构域将 C 端血红素结合 NEAT 结构域完美定位以进行血红素转移。这些数据，连同与 Hb 结合的孤立 N 端结构域的 2.3 分辨率晶体结构以及游离 IsdH 的小角度 X 射线散射，揭示了 IsdH 的多个结构域如何协作从 Hb 中剥离血红素。许多细菌病原体使用含有多个 NEAT 结构域和其他功能知之甚少的结构域的蛋白质从人类血红蛋白中获取铁。我们的结果表明，NEAT 结构域不是作为孤立的单元，而是可以集成到更高阶的架构中，该架构采用多个相互作用接口来有效地从宿主蛋白中提取血红素。
Background: IsdB and IsdH proteins from Staphylococcus aureus strip heme iron from human hemoglobin. Results: The IsdHhemoglobin complex shows how globin-binding and heme-binding NEAT domains of IsdH cooperate to remove heme from both chains of hemoglobin. Conclusion: The supradomain architecture of IsdH confers activity by precisely positioning the heme acceptor domain. Significance: Multiple IsdHhemoglobin interfaces may be targets for new antibiotics. Staphylococcus aureus causes life-threatening disease in humans. The S. aureus surface protein iron-regulated surface determinant H (IsdH) binds to mammalian hemoglobin (Hb) and extracts heme as a source of iron, which is an essential nutrient for the bacteria. However, the process of heme transfer from Hb is poorly understood. We have determined the structure of IsdH bound to human Hb by x-ray crystallography at 4.2 resolution, revealing the structural basis for heme transfer. One IsdH molecule is bound to each and Hb subunit, suggesting that the receptor acquires iron from both chains by a similar mechanism. Remarkably, two near iron transporter (NEAT) domains in IsdH perform very different functions. An N-terminal NEAT domain binds / globin through a site distant from the globin heme pocket and, via an intervening structural domain, positions the C-terminal heme-binding NEAT domain perfectly for heme transfer. These data, together with a 2.3 resolution crystal structure of the isolated N-terminal domain bound to Hb and small-angle x-ray scattering of free IsdH, reveal how multiple domains of IsdH cooperate to strip heme from Hb. Many bacterial pathogens obtain iron from human hemoglobin using proteins that contain multiple NEAT domains and other domains whose functions are poorly understood. Our results suggest that, rather than acting as isolated units, NEAT domains may be integrated into higher order architectures that employ multiple interaction interfaces to efficiently extract heme from host proteins.