Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1905-10. doi: 10.1073/pnas.1214943110. Epub 2013 Jan 14.
African trypanosomes are protected by a densely packed surface monolayer of variant surface glycoprotein (VSG). A haptoglobin-hemoglobin receptor (HpHbR) within this VSG coat mediates heme acquisition. HpHbR is also exploited by the human host to mediate endocytosis of trypanolytic factor (TLF)1 from serum, contributing to innate immunity. Here, the crystal structure of HpHbR from Trypanosoma congolense has been solved, revealing an elongated three α-helical bundle with a small membrane distal head. To understand the receptor in the context of the VSG layer, the dimensions of Trypanosoma brucei HpHbR and VSG have been determined by small-angle X-ray scattering, revealing the receptor to be more elongated than VSG. It is, therefore, likely that the receptor protrudes above the VSG layer and unlikely that the VSG coat can prevent immunoglobulin binding to the receptor. The HpHb-binding site has been mapped by single-residue mutagenesis and surface plasmon resonance. This site is located where it is readily accessible above the VSG layer. A single HbHpR polymorphism unique to human infective T. brucei gambiense has been shown to be sufficient to reduce binding of both HpHb and TLF1, modulating ligand affinity in a delicate balancing act that allows nutrient acquisition but avoids TLF1 uptake.
非洲锥虫被一层紧密堆积的变异表面糖蛋白 (VSG) 表面单层所保护。该 VSG 外壳内的一个触珠蛋白-血红蛋白受体 (HpHbR) 介导血红素的获取。HpHbR 也被人类宿主利用来介导来自血清的原虫溶素因子 (TLF)1 的内吞作用，有助于先天免疫。在这里，已经解决了来自刚果锥虫的 HpHbR 的晶体结构，揭示了一个带有小膜远端头部的细长三 α-螺旋束。为了在 VSG 层的背景下理解该受体，已经通过小角度 X 射线散射确定了布氏锥虫 HpHbR 和 VSG 的尺寸，表明受体比 VSG 更长。因此，受体很可能突出于 VSG 层之上，并且 VSG 层不太可能阻止免疫球蛋白与受体结合。通过单残基突变和表面等离子体共振映射了 HpHb 结合位点。该位点位于 VSG 层上方，很容易到达的位置。已经表明，仅在人类感染性 T. brucei gambiense 中存在的单个 HbHpR 多态性足以降低 HpHb 和 TLF1 的结合，从而在微妙的平衡作用中调节配体亲和力，允许营养物质的获取，但避免 TLF1 的摄取。
