Influenza hemagglutinin is spring-loaded by a metastable native conformation
Influenza hemagglutinin is spring-loaded by a metastable native conformation
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DOI：
10.1073/pnas.94.26.14306
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发表时间：
1997-12-23
影响因子：
11.1
通讯作者：
Kim, PS
中科院分区：
文献类型：
--
作者：
Carr, CM;Chaudhry, C;Kim, PS
包膜病毒通过蛋白质介导的膜融合进入细胞。对于流感病毒，膜融合由血凝素（HA）蛋白的构象状态调节，当暴露于细胞内体的酸性环境时，血凝素（HA）蛋白从天然（非融合）结构转换为融合活性（融合）构象。在这里，我们证明了HA在中性pH下的不稳定性，无论是热还是变性剂尿素，都会引发一种构象变化，这种构象变化在生物化学上与低pH引发的变化无法区分。在每种情况下，构象变化都与膜融合活性的诱导相一致，提供了形成融合结构的有力证据，这些结果表明HA的天然结构被困在亚稳态，并且融合构象通过天然结构的不稳定而释放。这种策略可能被其他包膜病毒共享，包括那些。在中性pH下进入细胞，可能对理解HIV感染的膜融合步骤有意义。
Enveloped viruses enter cells by protein-mediated membrane fusion. For influenza virus, membrane fusion is regulated by the conformational state of the hemagglutinin (HA) protein, which switches from a native (nonfusogenic) structure to a fusion-active (fusogenic) conformation when exposed to the acidic environment of the cellular endosome. Here we demonstrate that destabilization of HA at neutral pH, with either heat or the denaturant urea, triggers a conformational change that is biochemically indistinguishable from the change triggered by low pH. In each case, the conformational change is coincident with induction of membrane-fusion activity, providing strong evidence that the fusogenic structure is formed, These results indicate that the native structure of HA is trapped in a metastable state and that the fusogenic conformation is released by destabilization of native structure. This strategy may be shared by other enveloped viruses, including those. that enter the cell at neutral pH, and could have implications for understanding the membrane fusion step of HIV infection.