FUSION PORE DYNAMICS IN INFLUENZA HEMAGGLUTININ-MEDIATED MEMBRANE FUSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们利用壳理论(连续介质力学的一个分支)对流感血凝素介导的膜融合中的融合孔动力学进行了理论研究。目前最流行的膜融合模型是茎模型或半融合假说(1)。提出了膜融合是从形成一个中间膜结构开始的，在中间膜结构中，两个相互作用的膜的外层小叶融合，形成柄；而内叶紧密相对，形成隔膜。柄的侧向扩张在横隔膜上打开一个融合孔。融合孔的扩大将导致膜的完全融合。然而，已发现在HA介导膜融合过程中发生显著的囊泡(细胞)内容物泄漏[2]。内容物的泄漏与熔融孔闪烁(反复打开和关闭)有关。这些观察结果与茎模型所暗示的非泄漏聚变事件相矛盾。我们用壳理论研究了囊泡和病毒膜在水泡-流感病毒融合过程中融合孔的初始打开、孔闪烁和孔扩大的机制。我们建议在流感血凝素介导的膜融合中，融合孔动力学与所报道的内容泄漏之间的关系。(1)切尔诺莫尔迪克，L.V.，M.科兹洛夫。2005年。膜半融合：两步跨越鸿沟。牢房。123：375-382。(2)Bonnafous、P.和T.Stegmann。2000年。流感血凝素介导膜融合中的膜扰动和融合孔形成。J.Biol.化学。275：6160-6166。(3)Frolov，V.A.，A.Y.Dunina-Barkovskaya，A.V.Samsonov和J.Zimmerberg。2003年。流感血凝素介导融合早期膜通透性的变化。生物物理学，J，85：1725-1733.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We initiated a theoretical study of fusion pore dynamics in influenza hemagglutinin-mediated membrane fusion using shell theory (a branch of continuum mechanics). Currently the most popular model for membrane fusion is the stalk model, or hemifusion hypothesis (1). It proposed that membrane fusion starts with formation of an intermediate membrane structure, in which the outer leaflets of the two interacting membranes are fused, forming a stalk; while the inner leaflets are intimately apposed, forming a diaphragm. A lateral expansion of the stalk opens a fusion pore in the diaphragm. Enlargement of the fusion pore will lead to complete membrane fusion. However, it has been found that significant vesicle (cell) content leaking occurs during HA-mediated membrane fusion (2). The content leaking was shown to be correlated with fusion pore flickering (open and close repeatedly) (3). These observations contradict a non-leaking fusion event implied by the stalk model. We have used shell theory to work out mechanisms for initial opening of fusion pore, pore flickering, and pore enlargement for both vesicle and viral membranes in vesicle-influenza virus fusion. We suggest a relation between the fusion pore dynamics with the reported content leakage during influenza hemagglutinin-mediated membrane fusion. (1) Chernomordik, L.V., M. Kozlov. 2005. Membrane hemifusion: crossing a chasm in two leaps. Cell. 123:375-382. (2) Bonnafous, P., and T. Stegmann. 2000. Membrane perturbation and fusion pore formation in influenza hemagglutinin-mediated membrane fusion. J. Biol. Chem. 275:6160-6166. (3) Frolov, V.A., A.Y. Dunina-Barkovskaya, A.V. Samsonov, and J. Zimmerberg. 2003. Membrane permeability changes at early stages of influenza hemagglutinin-mediated fusion. Biophys, J, 85:1725-1733.