Dynamic, variable oligomerization and the trafficking of variant surface glycoproteins of Trypanosoma brucei,Traffic

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Dynamic, variable oligomerization and the trafficking of variant surface glycoproteins of Trypanosoma brucei
Traffic ( IF 3.6 ) Pub Date : 2021-06-07 , DOI: 10.1111/tra.12806
Khan Umaer _{1,

2} , Francisco Aresta-Branco _{3,

4} , Monica Chandra _{3,

5} , Monique van Straaten ₃ , Johan Zeelen ₃ , Karine Lapouge ₆ , Brandon Waxman ₁ , C Erec Stebbins ₃ , James D Bangs ₁

Affiliation

African trypanosomes cause disease in humans and livestock, avoiding host immunity by changing the expression of variant surface glycoproteins (VSGs); the major glycosylphosphatidylinositol (GPI) anchored antigens coating the surface of the bloodstream stage. Proper trafficking of VSGs is therefore critical to pathogen survival. The valence model argues that GPI anchors regulate progression and fate in the secretory pathway and that, specifically, a valence of two (VSGs are dimers) is critical for stable cell surface association. However, recent reports that the MITat1.3 (M1.3) VSG N-terminal domain (NTD) behaves as a monomer in solution and in a crystal structure challenge this model. We now show that the behavior of intact M1.3 VSG in standard in vivo trafficking assays is consistent with an oligomer. Nevertheless, Blue Native Gel electrophoresis and size exclusion chromatography-multiangle light scattering chromatography of purified full length M1.3 VSG indicates a monomer in vitro. However, studies with additional VSGs show that multiple oligomeric states are possible, and that for some VSGs oligomerization is concentration dependent. These data argue that individual VSG monomers possess different propensities to self-oligomerize, but that when constrained at high density to the cell surface, oligomeric species predominate. These results resolve the apparent conflict between the valence hypothesis and the M1.3 NTD VSG crystal structure.

中文翻译：

布氏锥虫的动态、可变寡聚化和变异表面糖蛋白的运输

非洲锥虫在人类和牲畜中引起疾病，通过改变变异表面糖蛋白 (VSG) 的表达来避免宿主免疫；主要的糖基磷脂酰肌醇 (GPI) 锚定抗原覆盖血流阶段的表面。因此，适当运输 VSG 对病原体存活至关重要。价模型认为 GPI 锚调节分泌途径中的进展和命运，特别是，二价（VSG 是二聚体）对于稳定的细胞表面结合至关重要。然而，最近有报道称 MITat1.3 (M1.3) VSG N 端结构域 (NTD) 在溶液和晶体结构中表现为单体，对这一模型提出了挑战。我们现在表明，完整的 M1.3 VSG 在标准体内贩运测定中的行为与寡聚体一致。尽管如此，纯化的全长 M1.3 VSG 的蓝色天然凝胶电泳和尺寸排阻色谱-多角度光散射色谱在体外表明单体。然而，对其他 VSG 的研究表明，多种寡聚状态是可能的，并且对于某些 VSG，寡聚化是浓度依赖性的。这些数据表明，单个 VSG 单体具有不同的自寡聚倾向，但是当以高密度限制在细胞表面时，寡聚物种占主导地位。这些结果解决了价假说和 M1.3 NTD VSG 晶体结构之间的明显冲突。对其他 VSG 的研究表明，多种寡聚状态是可能的，并且对于某些 VSG，寡聚化是浓度依赖性的。这些数据表明，单个 VSG 单体具有不同的自寡聚倾向，但是当以高密度限制在细胞表面时，寡聚物种占主导地位。这些结果解决了价假说和 M1.3 NTD VSG 晶体结构之间的明显冲突。对其他 VSG 的研究表明，多种寡聚状态是可能的，并且对于某些 VSG，寡聚化是浓度依赖性的。这些数据表明，单个 VSG 单体具有不同的自寡聚倾向，但是当以高密度限制在细胞表面时，寡聚物种占主导地位。这些结果解决了价假说和 M1.3 NTD VSG 晶体结构之间的明显冲突。

更新日期：2021-07-27

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