Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor.
Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor.
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DOI：
10.7554/elife.05553
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发表时间：
2014-12-12
期刊：
影响因子：
7.7
通讯作者：
Higgins MK
中科院分区：
文献类型：
--
作者：
Lane-Serff H;MacGregor P;Lowe ED;Carrington M;Higgins MK
非洲锥虫的结合珠蛋白-血红蛋白受体(HpHbR)允许获得血红蛋白，并提供了摄取锥虫溶解因子-1的途径，锥虫因子-1是对抗锥虫感染的天然免疫的媒介。在这项研究中，我们报道了布鲁氏锥虫HpHbR与人结合珠蛋白-血红蛋白(HpHb)的复合体的结构，揭示了沿着其膜远端一半延伸的细长的配体结合部位。这与结合珠蛋白和血红蛋白的β亚基相联系，显示了受体如何选择性地结合单个成分上的HPHb。糖基磷脂酰肌醇锚定的HPHbR的侧向移动性和受体上的∼500o扭结允许两个受体同时结合一个HPHb二聚体。事实上，由于二价结合增加了配体亲和力，锥虫以比单体HPHb低得多的浓度摄取二聚体HPHb。因此，该结构揭示了锥体摄取配体和天然免疫因子的分子基础，并确定了在复杂的锥体细胞表面允许有效摄取配体的适应。DOI：http://dx.doi.org/10.7554/eLife.05553.001非洲锥虫是一组单细胞寄生虫，是撒哈拉以南非洲畜牧业农民的主要担忧。它们由采采蝇携带，可在家畜中引起疾病，通过减少生长而降低生产力，并最终可能导致死亡。这些寄生虫被一层致密的蛋白质覆盖，通过阻止免疫细胞识别它们来帮助它们逃避宿主的免疫系统。人类通过利用生活方式中的弱点进化出对许多锥虫物种的免疫力。锥虫需要从宿主那里获得血红素--一种在蛋白质血红蛋白中发现的分子--才能生存。在血浆中，发现血红蛋白与一种称为结合珠蛋白的载体蛋白有关。为了获得血红素，寄生虫有一种名为HpHbR的蛋白质与这些结合珠蛋白-血红蛋白‘复合体’结合。然而，在人类体内，有两种名为TLF的蛋白质复合体，其中含有血红蛋白和一种与结合珠蛋白相关的蛋白质。TLF还能与HpHbR结合，并被带入寄生虫体内。一旦进入体内，TLF会导致称为溶酶体的内部隔室膨胀，从而导致锥虫的死亡。布鲁氏锥虫的两个亚种是唯一感染人类的锥体，因为它们可以克服TLF1防御。然而，TLFS如何在分子水平上导致细胞死亡的细节尚不清楚。Lane-SERff等人。使用一种名为x射线结晶学的技术，从与结合珠蛋白-血红蛋白复合体结合的布鲁氏毛虫中产生HpHbR蛋白的3D图像。这些图像显示，HPHbR被拉长，只有当它们作为复合体结合在一起时，它才能与血红蛋白和结合珠蛋白结合。图像还显示，HpHbR的形状使其能够将覆盖锥虫的保护层中的蛋白质分开。这使得结合珠蛋白-血红蛋白复合体能够与HpHbR结合，但在人类中也使HpHbR更有可能与TLF1结合。这些发现可能有助于指导未来保护人类和牲畜免受锥虫引起的疾病的努力。DOI：http://dx.doi.org/10.7554/eLife.05553.002
The haptoglobin-haemoglobin receptor (HpHbR) of African trypanosomes allows acquisition of haem and provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. In this study, we report the structure of Trypanosoma brucei HpHbR in complex with human haptoglobin-haemoglobin (HpHb), revealing an elongated ligand-binding site that extends along its membrane distal half. This contacts haptoglobin and the β-subunit of haemoglobin, showing how the receptor selectively binds HpHb over individual components. Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a ∼50o kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer. Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding. The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface. DOI: http://dx.doi.org/10.7554/eLife.05553.001 African Trypanosomes are a group of single-celled parasites that are a major concern for livestock farmers in sub-Saharan Africa. They are carried by the tsetse fly and can cause disease in domestic livestock that diminishes productivity through reduced growth, and may ultimately lead to death. The parasites are coated in a dense layer of protein that help them evade the host’s immune system by preventing immune cells from identifying them. Humans have evolved immunity to many trypanosome species by exploiting a weakness in their lifestyle. Trypanosomes need to get haem—a molecule found in the protein haemoglobin—from their host to survive. In blood plasma, haemoglobin is found associated with a carrier protein called haptoglobin. To acquire haem, the parasites have a protein called HpHbR that binds to these haptoglobin-haemoglobin ‘complexes’. However, in humans there are two complexes of proteins called TLFs that contain haemoglobin and a protein related to haptoglobin. The TLFs are also able to bind to HpHbR and are taken into the parasite. Once inside, TLFs cause internal compartments called lysosomes to swell, which leads to the death of the trypanosome. Two subspecies of Trypanosoma brucei are the only trypanosomes that infect humans as they can overcome the TLF1 defense. However, the details of how TLFs cause cell death at the molecular level are not clear. Lane-Serff et al. used a technique called x-ray crystallography to generate 3-D images of the HpHbR protein from T. brucei bound to the haptoglobin-haemoglobin complexes. These images show that HpHbR is elongated so that it only binds to haemoglobin and haptoglobin when they are together as a complex. The images also reveal that the shape of HpHbR enables it to hold apart the proteins in the protective layer that coats the trypanosome. This allows the haptoglobin-haemoglobin complex to bind to HpHbR, but in humans also makes HpHbR more likely to bind to TLF1. These findings may help to guide future efforts to protect humans and livestock from the diseases caused by trypanosomes. DOI: http://dx.doi.org/10.7554/eLife.05553.002