Shr of group A streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin.
Shr of group A streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin.
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DOI：
10.1111/j.1365-2958.2010.07367.x
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发表时间：
2010-11
影响因子：
3.6
通讯作者：
Eichenbaum Z
中科院分区：
文献类型：
--
作者：
Ouattara M;Cunha EB;Li X;Huang YS;Dixon D;Eichenbaum Z
越来越多的证据表明，具有 NEAr 转运蛋白 (NEAT) 结构域的表面或分泌蛋白在血红素获取和穿过革兰氏阳性菌细胞膜的运输中发挥着核心作用。 A 组链球菌 (GAS) 是一种 β 溶血性人类病原体，表达 NEAT 蛋白 Shr，该蛋白与多种血红素蛋白和细胞外基质 (ECM) 成分结合。 Shr 是一种复杂的膜锚定蛋白，具有独特的 N 末端结构域 (NTD) 和两个由富含亮氨酸的重复区域分隔的 NEAT 结构域。在这项研究中，我们对 Shr 中的功能域进行了分析。我们表明，Shr 在溶液中获得血红素，并进一步还原血红素铁；这是 NEAT 蛋白减少血红素的第一份报告。更具体地说，我们证明 Shr 的两个组成 NEAT 结构域都负责结合血红素，尽管它们缺少其他血红素结合 NEAT 结构域的配体结合口袋中发现的关键酪氨酸残基。进一步的研究表明，Shr NTD 内先前未描述的区域与高铁血红蛋白相互作用。然而，Shr NEAT 结构域对高铁血红蛋白的结合没有显着贡献，但介导与 ECM 成分纤连蛋白和层粘连蛋白的结合。发现含有 NTD 加上第一个 NEAT 结构域的蛋白质片段足以直接将血红素与高铁血红蛋白隔离。将这些体外研究结果与体内生物学功能相关联，突变体分析确定了 Shr 在高铁血红蛋白作为唯一铁来源的 GAS 生长中的作用，并表明至少一个 NEAT 结构域对于高铁血红蛋白的利用是必需的。我们认为 Shr 是一组新的 NEAT 复合蛋白的原型，这些复合蛋白参与在化脓性链球菌和诺氏梭菌中发现的血红素摄取。
A growing body of evidence suggests that surface or secreted proteins with NEAr Transporter (NEAT) domains play a central role in heme acquisition and trafficking across the cell envelope of Gram-positive bacteria. Group A Streptococcus (GAS), a β-hemolytic human pathogen, expresses a NEAT protein, Shr, which binds several hemoproteins and extracellular matrix (ECM) components. Shr is a complex, membrane-anchored protein, with a unique N-terminal domain (NTD) and two NEAT domains separated by a central leucine-rich repeat region. In this study we have carried out an analysis of the functional domains in Shr. We show that Shr obtains heme in solution and furthermore reduces the heme iron; this is the first report of heme reduction by a NEAT protein. More specifically, we demonstrate that both of the constituent NEAT domains of Shr are responsible for binding heme, although they are missing a critical tyrosine residue found in the ligand-binding pocket of other heme-binding NEAT domains. Further investigations show that a previously undescribed region within the Shr NTD interacts with methemoglobin. Shr NEAT domains, however, do not contribute significantly to the binding of methemoglobin but mediate binding to the ECM components fibronectin and laminin. A protein fragment containing the NTD plus the first NEAT domain was found to be sufficient to sequester heme directly from methemoglobin. Correlating these in vitro findings to in vivo biological function, mutants analysis establishes the role of Shr in GAS growth with methemoglobin as a sole source of iron, and indicates that at least one NEAT domain is necessary for the utilization of methemoglobin. We suggest that Shr is the prototype of a new group of NEAT composite proteins involved in heme uptake found in pyogenic streptococci and Clostridium novyi.
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影响因子：
3.2
作者：
Dryla, Agnieszka;Hoffmann, Bernd;Nagy, Eszter
通讯作者：
Nagy, Eszter
影响因子：
3.1
作者：
Eichenbaum, Z;Muller, E;Scott, JR
通讯作者：
Scott, JR
影响因子：
3.1
作者：
Lei, BF;Liu, MY;Musser, JM
通讯作者：
Musser, JM
影响因子：
4.1
作者：
BROWN, SB;LANTZKE, IR
通讯作者：
LANTZKE, IR
影响因子：
3.2
作者：
Kunkle, Carey A.;Schmitt, Michael P.
通讯作者：
Schmitt, Michael P.