Boulton I C, Gorringe A R, Shergill J K, Joannou C L, Evans R W
Centre for Applied Microbiology and Research, Salisbury, SP4 0JG, UK.
J Theor Biol. 1999 Jun 21;198(4):497-505. doi: 10.1006/jtbi.1999.0928.
Iron is an essential nutrient for all organisms and consequently, the ability to bind transferrin and sequester iron from his source constitutes a distinct advantage to a blood-borne bacterial pathogen. Levels of free iron are strictly limited in human serum, largely through the action of the iron-binding protein transferrin. The acquisition of trasferrin-iron is coincident with pathogenicity among Neisseria species and a limited number of other pathogens of human and veterinary significance. In Neisseria meningitidis, transferrin binding relies on two co-expressed, outer membrane proteins distinct in aspects of both structure and function. These proteins are independently and simultaneously capable of binding human transferrin and both are required for the optimal uptake of iron from this source. It has been established that transferrin-binding proteins (designated TbpA and TbpB) form a discrete, specific complex which may be composed of a transmembrane species (composed of the TbpA dimer) associated with a single surface-exposed lipoprotein (TbpB). This more exposed protein is capable of selectively binding iron-saturated transferrin and the receptor complex has ligand-binding properties which are distinct from either of its components. Previous in vivo analyses of N. gonorrhoeae, which utilizes a closely related transferrin-iron uptake system, indicated that this receptor exists in several conformations influenced in part by the presence (or absence) of transferrin. Here we propose a dynamic model of the meningococcal transferrin receptor which is fully consistent with the current data concerning this subject. We suggest that TbpB serves as the initial binding site for iron-saturated transferrin and brings this ligand close to the associated transmembrane dimer, enabling additional binding events and orientating transferrin over the dual TbpA pores. The antagonistic association of these receptor proteins with a single ligand molecule may also induce conformational change in transferrin, thereby favouring the release of iron. As, in vivo, transferrin may have iron in one or both lobes, this dynamic molecular arrangement would enable iron uptake from either iron-binding site. In addition, the predicted molecular dimensions of the putative TbpA dimer and hTf are fully consistent with these proposals. Given the diverse data used in the formulation of this model and the consistent characteristics of transferrin binding among several significant Gram-negative pathogens, we speculate that such receptor-ligand interactions may be, at least in part, conserved between species. Consequently, this model may be applicable to bacteria other than N. meningitidis.
铁是所有生物体必需的营养物质，因此，对于血源性病原体而言，能够结合转铁蛋白并从其来源中螯合铁是一项显著优势。人血清中的游离铁水平受到严格限制，这主要是通过铁结合蛋白转铁蛋白的作用实现的。获取转铁蛋白结合铁与脑膜炎奈瑟菌属以及其他一些对人和兽医具有重要意义的病原体的致病性相关。在脑膜炎奈瑟菌中，转铁蛋白结合依赖于两种共同表达的外膜蛋白，它们在结构和功能方面都有所不同。这些蛋白能够独立且同时结合人转铁蛋白，并且都是从该来源最佳摄取铁所必需的。已经确定，转铁蛋白结合蛋白（称为TbpA和TbpB）形成一个离散的、特异性复合物，该复合物可能由与单个表面暴露脂蛋白（TbpB）相关的跨膜物种（由TbpA二聚体组成）构成。这种更易暴露的蛋白能够选择性结合铁饱和的转铁蛋白，并且受体复合物具有与其任何一个组分都不同的配体结合特性。先前对利用密切相关的转铁蛋白 - 铁摄取系统的淋病奈瑟菌进行的体内分析表明，该受体存在几种构象，部分受转铁蛋白存在（或不存在）的影响。在此，我们提出了一个脑膜炎球菌转铁蛋白受体的动态模型，该模型与关于该主题的当前数据完全一致。我们认为TbpB作为铁饱和转铁蛋白的初始结合位点，并将该配体带到相关的跨膜二聚体附近，从而实现额外的结合事件并使转铁蛋白在双TbpA孔上定向排列。这些受体蛋白与单个配体分子的拮抗结合也可能诱导转铁蛋白的构象变化，从而有利于铁的释放。由于在体内，转铁蛋白的一个或两个叶可能含有铁，这种动态分子排列将能够从任何一个铁结合位点摄取铁。此外，推测的TbpA二聚体和人转铁蛋白的预测分子尺寸与这些提议完全一致。鉴于在构建该模型时使用了多种数据以及几种重要革兰氏阴性病原体之间转铁蛋白结合的一致特征，我们推测这种受体 - 配体相互作用可能至少在部分程度上在物种之间是保守的。因此，该模型可能适用于除脑膜炎奈瑟菌之外的细菌。
