Palermo Laura M, Porotto Matteo, Greengard Olga, Moscona Anne
Department of Pediatrics, Weill Medical College of Cornell University, 515 East 71st St., Box 309, New York, NY 10021, USA.
J Virol. 2007 Sep;81(17):9152-61. doi: 10.1128/JVI.00888-07. Epub 2007 Jun 13.
Paramyxoviruses, including the childhood respiratory pathogen human parainfluenza virus type 3 (HPIV3), possess an envelope protein hemagglutinin-neuraminidase (HN) that has receptor-cleaving (neuraminidase), as well as receptor-binding, activity. HN is a type II transmembrane glycoprotein, present on the surface of the virus as a tetramer composed of two dimers. HN is also essential for activating the fusion protein (F) to mediate merger of the viral envelope with the host cell membrane. This initial step of viral entry occurs at the host cell surface at neutral pH. The HN molecule carries out these three different critical activities at specific points in the process of viral entry, and understanding the regulation of these activities is key for the design of strategies that block infection. One bifunctional site (site I) on the HN of HPIV3 possesses both receptor binding and neuraminidase activities, and we recently obtained experimental evidence for a second receptor binding site (site II) on HPIV3 HN. Mutation of HN at specific residues at this site, which is next to the HN dimer interface, confers enhanced fusion properties, without affecting neuraminidase activity or receptor binding at neutral pH. We now demonstrate that mutations at this site II, as well as at site I, confer pH dependence on HN's receptor avidity. These mutations permit pH to modulate the binding and fusion processes of the virus, potentially providing regulation at specific stages of the viral life cycle.
副粘病毒，包括儿童呼吸道病原体3型人副流感病毒（HPIV3），拥有一种包膜蛋白血凝素神经氨酸酶（HN），该蛋白具有受体切割（神经氨酸酶）以及受体结合活性。HN是一种II型跨膜糖蛋白，以由两个二聚体组成的四聚体形式存在于病毒表面。HN对于激活融合蛋白（F）以介导病毒包膜与宿主细胞膜的融合也至关重要。病毒进入的这一初始步骤发生在中性pH值的宿主细胞表面。HN分子在病毒进入过程的特定阶段执行这三种不同的关键活性，而了解这些活性的调节对于设计阻断感染的策略至关重要。HPIV3的HN上的一个双功能位点（位点I）同时具有受体结合和神经氨酸酶活性，并且我们最近获得了HPIV3 HN上第二个受体结合位点（位点II）的实验证据。该位点位于HN二聚体界面旁边，在此位点特定残基处的HN突变赋予了增强的融合特性，而不影响神经氨酸酶活性或中性pH值下的受体结合。我们现在证明，该位点II以及位点I处的突变赋予了HN受体亲和力对pH的依赖性。这些突变允许pH调节病毒的结合和融合过程，这可能在病毒生命周期的特定阶段提供调控。
