Valency and Geometry of multivalent Glycolipid binding as cellular targeting mechnaism in viral infection

多价糖脂结合作为病毒感染细胞靶向机制的化合价和几何结构

• 批准号: 421460908
• 负责人: Professor Dr. Helge Ewers
• 金额: --
• 依托单位: AG Ewers - Membranbiochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/421460908?language=en
• 关键词: Valency; Geometry; multivalent; Glycolipid; binding

Glycolipid-binding viruses such as the DNA tumorvirus SV40 use clathrin-independent uptake pathways to enter cells for productive infection. To do so, they exploit the multivalent binding of SV40 to the glycolipid GM1 for membrane deformation leading to endocytosis. However, the physicochemical mechanism behind this pathway remains poorly understood and it is unclear, whether all glycolipid-binding polyomaviridae follow a similar route. At the same time, it remains unclear, why the globular GM1-binding SV40 virion is trafficked to the endoplasmatic reticulum (ER) leading to productive infection, while the likewise GM1-clustering Cholera toxin beta subunit (CTxB) ends up in the Golgi apparatus and unclustered GM1 molecules recycle to the plasma membrane. We aim here to find out, whether the globular geometric arrangement of viral ligands to carbohydrate binding sites is a general mechanism for membrane deformation in viral infection and how the number, nature and arrangement of carbohydrate binding sites controls cellular uptake and infection of virions. To do so, we will combine a number of live-cell, in situ and in vitro assays with high resolution and X-ray microscopy.

糖脂结合病毒，如DNA肿瘤病毒SV40，使用不依赖于笼蛋白的摄取途径进入细胞进行生产性感染。为了做到这一点，他们利用SV40与糖脂GM1的多价结合来使膜变形，导致内吞作用。然而，这一途径背后的物理化学机制仍然知之甚少，也不清楚是否所有的糖脂结合多核病毒科都遵循类似的途径。同时，目前尚不清楚为什么与GM1结合的球形SV40病毒粒子被运输到内质网(ER)导致生产性感染，而同样GM1聚集的霍乱毒素β亚单位(CTxB)最终进入高尔基体，未聚集的GM1分子循环到质膜。我们的目的是找出病毒配体与糖类结合部位的球形几何排列是否是病毒感染中膜变形的一般机制，以及碳水化合物结合部位的数量、性质和排列如何控制细胞对病毒粒子的摄取和感染。为了做到这一点，我们将结合一些活细胞、原位和体外分析与高分辨率和X射线显微镜。