Cholesterol enhances influenza binding avidity by controlling nanoscale receptor clustering.
Cholesterol enhances influenza binding avidity by controlling nanoscale receptor clustering.
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DOI：
10.1039/c7sc03236f
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发表时间：
2018-02-28
期刊：
影响因子：
8.4
通讯作者：
Kasson PM
中科院分区：
文献类型：
--
作者：
Goronzy IN;Rawle RJ;Boxer SG;Kasson PM
单病毒结合测量和模拟显示胆固醇介导的受体聚集如何控制流感病毒膜结合亲和力。流感病毒通过与细胞表面上的唾液酸化聚糖结合来感染细胞。虽然这些聚糖的化学结构决定了血凝素-聚糖结合亲和力，但双分子亲和力较弱，因此结合是亲合力主导的，并由多价相互作用驱动。在这里，我们表明，膜空间组织可以控制病毒结合。使用单病毒荧光显微镜，我们证明了目标膜的甾醇组合物以剂量依赖性方式增强病毒结合亲和力。结合显示出对流感病毒受体浓度的合作依赖性，如对于多价相互作用所预期的。令人惊讶的是，甾醇促进病毒结合的能力与其在模型系统中支持液-液相分离的能力无关。我们通过分子动力学模拟对这一观察结果进行了分子解释，我们发现胆固醇促进了小规模的鞘糖脂受体簇。我们提出了一个模型，胆固醇命令的鞘糖脂受体的单体状态，减少受体协会的熵罚，从而有利于多聚体复合物没有相分离。该模型解释了胆固醇和其他固醇如何控制流感病毒膜受体的空间组织并增加病毒结合亲和力。这一发现的自然结果是细胞质膜中的局部胆固醇浓度可能改变流感病毒粒子的结合亲合力。此外，我们的研究结果表明，胆固醇依赖性膜组织的形式，不涉及脂筏，这表明胆固醇对细胞膜异质性的影响可能是几个不同因素的相互作用。
Single-virus binding measurements and simulations show how cholesterol-mediated clustering of receptors controls influenza membrane-binding avidity. Influenza virus infects cells by binding to sialylated glycans on the cell surface. While the chemical structure of these glycans determines hemagglutinin–glycan binding affinity, bimolecular affinities are weak, so binding is avidity-dominated and driven by multivalent interactions. Here, we show that membrane spatial organization can control viral binding. Using single-virus fluorescence microscopy, we demonstrate that the sterol composition of the target membrane enhances viral binding avidity in a dose-dependent manner. Binding shows a cooperative dependence on concentration of receptors for influenza virus, as would be expected for a multivalent interaction. Surprisingly, the ability of sterols to promote viral binding is independent of their ability to support liquid–liquid phase separation in model systems. We develop a molecular explanation for this observation via molecular dynamics simulations, where we find that cholesterol promotes small-scale clusters of glycosphingolipid receptors. We propose a model whereby cholesterol orders the monomeric state of glycosphingolipid receptors, reducing the entropic penalty of receptor association and thus favoring multimeric complexes without phase separation. This model explains how cholesterol and other sterols control the spatial organization of membrane receptors for influenza and increase viral binding avidity. A natural consequence of this finding is that local cholesterol concentration in the plasma membrane of cells may alter the binding avidity of influenza virions. Furthermore, our results demonstrate a form of cholesterol-dependent membrane organization that does not involve lipid rafts, suggesting that cholesterol's effect on cell membrane heterogeneity is likely the interplay of several different factors.
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DOI：
10.1021/acs.jpcb.6b07142
发表时间：
2017-04-20
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Gu RX;Ingólfsson HI;de Vries AH;Marrink SJ;Tieleman DP
通讯作者：
Tieleman DP
影响因子：
4.1
作者：
Levental, Ilya;Byfield, Fitzroy J.;Janmey, Paul A.
通讯作者：
Janmey, Paul A.
影响因子：
5.5
作者：
Lopez, Cesar A.;Sovova, Zofie;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.
影响因子：
64.8
作者：
Imai, Masaki;Watanabe, Tokiko;Hatta, Masato;Das, Subash C.;Ozawa, Makoto;Shinya, Kyoko;Zhong, Gongxun;Hanson, Anthony;Katsura, Hiroaki;Watanabe, Shinji;Li, Chengjun;Kawakami, Eiryo;Yamada, Shinya;Kiso, Maki;Suzuki, Yasuo;Maher, Eileen A.;Neumann, Gabriele;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro
DOI：
10.1126/science.1213362
发表时间：
2012-06-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Herfst S;Schrauwen EJ;Linster M;Chutinimitkul S;de Wit E;Munster VJ;Sorrell EM;Bestebroer TM;Burke DF;Smith DJ;Rimmelzwaan GF;Osterhaus AD;Fouchier RA
通讯作者：
Fouchier RA