Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms
Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms
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流感血凝素通过两种连续的膜内机制驱动病毒进入
DOI：
10.1073/pnas.1914188117
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kasson, Peter M.
中科院分区：
文献类型：
--
作者：
Pabis, Anna;Rawle, Robert J.;Kasson, Peter M.
包膜病毒通过病毒包膜和细胞膜之间的膜融合过程进入细胞。对于流感病毒，突变数据表明，血凝素蛋白的膜插入部分在实现融合中起关键作用。与相对较好理解的胞外域相反，对流感血凝素驱动融合的膜内机制的预测性机制理解一直是难以捉摸的。我们使用分子动力学模拟全长血凝素蛋白脂质体和脂质双层之间的融合来分析这些机制。在我们的模拟中，血凝素首先在膜内起作用以增加脂质尾突出并促进柄形成，然后起作用以接合每个膜的远端小叶并促进柄加宽、弯曲和最终融合。这两个连续的机制，一个发生在茎形成之前，一个发生在茎形成之后，与我们的实验测量不同大小的脂质体的单病毒融合动力学是一致的。所得到的模型也有助于解释和整合以前的突变和生物物理数据，特别是融合肽N末端的突变敏感性和跨膜结构域的长度敏感性。我们假设其他包膜病毒的进入也可能使用酰基尾暴露的顺序过程，然后是膜弯曲和远端小叶接合。
Enveloped viruses enter cells via a process of membrane fusion between the viral envelope and a cellular membrane. For influenza virus, mutational data have shown that the membrane-inserted portions of the hemagglutinin protein play a critical role in achieving fusion. In contrast to the relatively well-understood ectodomain, a predictive mechanistic understanding of the intramembrane mechanisms by which influenza hemagglutinin drives fusion has been elusive. We used molecular dynamics simulations of fusion between a full-length hemagglutinin proteoliposome and a lipid bilayer to analyze these mechanisms. In our simulations, hemagglutinin first acts within the membrane to increase lipid tail protrusion and promote stalk formation and then acts to engage the distal leaflets of each membrane and promote stalk widening, curvature, and eventual fusion. These two sequential mechanisms, one occurring before stalk formation and one after, are consistent with our experimental measurements of single-virus fusion kinetics to liposomes of different sizes. The resulting model also helps explain and integrate previous mutational and biophysical data, particularly the mutational sensitivity of the fusion peptide N terminus and the length sensitivity of the transmembrane domain. We hypothesize that entry by other enveloped viruses may also use sequential processes of acyl tail exposure, followed by membrane curvature and distal leaflet engagement.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
流感血凝素融合肽位置 1 的特定点突变表现出半融合表型。
影响因子：
3.3
作者：
Qiao,H;Armstrong,RT;Melikyan,GB;Cohen,FS;White,JM
通讯作者：
White,JM
囊泡融合的茎机制
DOI：
--
发表时间：
1989
期刊：
European Biophysics Journal
影响因子：
--
作者：
M. Kozlov;S. Leikin;L. Chernomordik;V. Markin;Y. Chizmadzhev
通讯作者：
Y. Chizmadzhev
影响因子：
3.4
作者：
Kozlovsky, Y;Chernomordik, LV;Kozlov, MM
通讯作者：
Kozlov, MM
DOI：
10.1083/jcb.200103005
发表时间：
2001-11-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Markovic I;Leikina E;Zhukovsky M;Zimmerberg J;Chernomordik LV
通讯作者：
Chernomordik LV