Structure of the primed paramyxovirus fusion protein.
Structure of the primed paramyxovirus fusion protein.
复制标题
引发的副粘病毒融合蛋白的结构。
DOI：
10.1073/pnas.1214903109
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发表时间：
2012
影响因子：
11.1
通讯作者：
Plemper,RichardKarl
中科院分区：
文献类型：
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作者：
Steinhauer,DavidA;Plemper,RichardKarl
具有脂质包膜的病毒必须将其膜与宿主细胞的膜融合以转移其基因组并引发感染。根据病毒的不同，膜融合过程可以发生在质膜上，也可以发生在病毒颗粒内化后的细胞膜上。毫不奇怪，负责膜融合的病毒蛋白是高度多样化的，融合过程的触发机制也是如此；然而，随着我们对膜融合的理解的发展，共同的主题已经出现。特别是，在融合前和融合后构象的病毒融合蛋白（F蛋白；VFPs）的高分辨率结构的扩展库推动了该领域的发展。从这些，我们知道许多vfp在融合过程中经历了实质性的构象变化，形成高度稳定的棒状结构将膜拉到一起（1-3）。尽管如此，对于流感HA以外的vfp(4-7)，在病毒生命周期中采用的所有三种主要静态构象（未裂解预融合、引物预融合和融合后）的高分辨率结构仍然不完整。这些限制阻碍了我们对病毒融合机制的深入了解，与流感病毒不同，病毒在中性ph下从质膜进入细胞。在《美国国家科学院院刊》（PNAS）的一篇开创性报告中(8)，Welch等人解决了副流感病毒5 （PIV5）的裂解，预融合形式的F蛋白的高分辨率x射线晶体结构。这通过提供对副粘病毒进入的理解中必不可少的缺失环节而改变了事态。结合这些实验室以前的工作（9,10），新的结构现在为我们提供了副粘病毒F蛋白的所有三种主要静态构象的完整集合（图1），这是代表多年努力的杰作（9,10）。这构成了另一个基本的构建块，在此基础上，我们可以更广泛地了解不同的病毒如何启动其表面糖蛋白来介导细胞进入并引发感染。除了提高我们对病毒生物学的分子知识，目前的成就将进一步开发旨在抑制膜融合的抗病毒药物。在过去的十年中，我们对vfp的结构和机制理解的扩展使得它们可以分为I、II和III类（11,12）。我们在这里重点关注I型vfp，包括流感HA和副粘病毒F蛋白，以及其他主要人类病原体的vfp，如HIV Env和埃博拉病毒GP。I型vfp的特征包括最初的合成和折叠成寡聚前体结构，这需要蛋白水解加工成成熟的形式，以启动膜融合电位和病毒传染性（13-16）。每个单体直接与内部疏水区域（“融合肽”）相邻，然后形成膜锚定亚基新释放的n端部分。当它被蛋白水解激活时，预融合构象必须由外部刺激触发，如副粘病毒中细胞受体的接触，或流感中核内体的酸性环境，以经历驱动膜融合过程的广泛结构重排（图1）。因此，在病毒复制周期的过程中，F蛋白至少采用三种不同的静态构象，这些构象以及从一种结构到另一种结构的转变对病毒进入至关重要。伴随流感HA裂解激活的结构重排揭示了随后的融合触发…
Viruses with lipid envelopes must fuse their membranes with those of host cells to transfer their genomes and initiate infection. Depending on the virus, the membrane fusion process can occur at the plasma membrane, or at intracellular membranes following the internalization of virus particles. Not surprisingly, the viral proteins responsible for membrane fusion are highly diverse, as are the mechanisms by which the fusion processes can be triggered; however, common themes have emerged as our understanding of membrane fusion has developed. In particular, an expanding repertoire of high-resolution structures of viral fusion proteins (F proteins; VFPs) in pre-and postfusion conformations has driven the field forward. From these, we know that many VFPs undergo substantial conformational changes during fusion, forming highly stable rod-like structures to draw the membranes together (1–3). Despite this, for VFPs other than influenza HA (4–7), highresolution structures for all three major static conformations adopted during the virus life cycle, uncleaved prefusion, primed prefusion and postfusion, have remained incomplete. These limitations have hindered our development of insights into the fusion mechanism of viruses that, unlike influenza virus, enter cells at the plasma membrane at neutral pH. In a groundbreaking report in PNAS (8), Welch et al. solve the high-resolution X-ray crystal structure of the cleaved, prefusion form of the F protein of parainfluenza virus 5 (PIV5). This alters the state of affairs by providing an essential missing link in the understanding of paramyxovirus entry. In conjunction with previous work by these laboratories (9, 10), the new structure now affords us with a complete set of all three major static conformations of paramyxovirus F proteins (Fig. 1), a tour de force representing many years of effort (9, 10). This constitutes another fundamental building block on which we can establish a broader appreciation of how different viruses prime their surface glycoproteins to mediate cell entry and initiate infection. In addition to advancing our molecular knowledge of virus biology, the present achievement will further the educated development of antiviral drugs designed to inhibit membrane fusion. During the past decade, the expansion of our structural and mechanistic understanding of VFPs has allowed for their grouping into type I, II, and III classes (11, 12). We focus here on the type I VFPs that include influenza HA and paramyxovirus F proteins, as well as VFPs of other major human pathogens such as HIV Env and Ebola virus GP. Hallmarks of type I VFPs include initial synthesis and folding into an oligomeric precursor structure, which requires proteolytic processing into a mature form to prime the membrane fusion potential and virus infectivity (13–16). Each monomer is cleaved directly adjacent to an internal hydrophobic domain, the “fusion peptide,” which then forms the newly liberated N-terminal section of the membrane-anchored subunit. When it has been activated by proteolysis, the prefusion conformations must be triggered by external stimuli such as engagement of a cellular receptor in the case of paramyxoviruses, or the acidic environment of an endosome as found with influenza, to undergo the extensive structural rearrangements that drive the membrane fusion process (Fig. 1). Therefore, over the course of the virus replication cycle, the F proteins adopt at least three distinct static conformations, which are, along with the transitions from one structure to the next, critical for virus entry. The structural rearrangements that accompany cleavage activation of influenza HA are revealing with regard to the subsequent triggering of fusion …