High-Speed AFM Reveals Molecular Dynamics of Human Influenza A Hemagglutinin and Its Interaction with Exosomes
High-Speed AFM Reveals Molecular Dynamics of Human Influenza A Hemagglutinin and Its Interaction with Exosomes
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DOI：
10.1021/acs.nanolett.0c01755
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发表时间：
2020-09-09
期刊：
影响因子：
10.8
通讯作者：
Wong, Richard W.
中科院分区：
文献类型：
--
作者：
Lim, Keesiang;Kodera, Noriyuki;Wong, Richard W.
甲型流感血凝素(HA)是调节宿主嗜性和病毒感染性的重要毒力因子之一。目前，HA融合基因转化的机制尚不清楚。在这里，我们使用高速原子力显微镜(HS-AFM)来破译HA的分子动力学及其与外切体的相互作用。我们的数据表明，HA在中性缓冲液中的天然构象是椭圆形的，而在酸性缓冲液中HA经历了构象变化。HS-AFM对融合转变的实时观察表明，这一机制可能符合“去老化”模型，HA中间体呈Y形。在酸性缓冲液中，透明质酸与外切体之间的牢固相互作用表明，融合肽插入到外切体层中，随后破坏外切体的稳定，导致外切体变形或断裂，释放外切体内容物。相反，在中性缓冲液中，HA外切体的相互作用很弱，因为这种相互作用是通过HA受体结合部位和外切体上的受体之间的弱键来调节的。
Influenza A hemagglutinin (HA) is one of the crucial virulence factors that mediate host tropism and viral infectivity. Presently, the mechanism of the fusogenic transition of HA remains elusive. Here, we used high-speed atomic force microscopy (HS-AFM) to decipher the molecular dynamics of HA and its interaction with exosomes. Our data reveal that the native conformation of HA in the neutral buffer is ellipsoidal, and HA undergoes a conformational change in an acidic buffer. Real-time visualization of the fusogenic transition by HS-AFM suggests that the mechanism is possibly fit to the "uncaging" model, and HA intermediate appears as Y-shaped. A firm interaction between the HA and exosome in an acidic buffer indicates the insertion of a fusion peptide into the exosomal layer and subsequently destabilizes the layer, resulting in the deformation or rupture of exosomes, releasing exosomal contents. In contrast, the HA exosome interaction is weak in a neutral buffer because the interaction is mediated by weak bonds between the HA receptor-binding site and receptors on the exosome.