Crystal Structure of the Herpesvirus Inner Tegument Protein UL37 Supports Its Essential Role in Control of Viral Trafficking
Crystal Structure of the Herpesvirus Inner Tegument Protein UL37 Supports Its Essential Role in Control of Viral Trafficking
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DOI：
10.1128/jvi.00163-14
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发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Heldwein, Ekaterina E.
中科院分区：
文献类型：
--
作者：
Pitts, Jared D.;Klabis, Jenifer;Heldwein, Ekaterina E.
在疱疹病毒感染的细胞中，两种衣壳相关或内层蛋白UL 37和UL 36通过尚不清楚的机制控制衣壳的胞质运输。在这里，我们报告的晶体结构的N-末端一半的UL 37从伪狂犬病病毒，α疱疹病毒密切相关的单纯疱疹病毒和水痘带状疱疹病毒。该结构是任何α疱疹病毒内层蛋白的第一个结构，揭示了一个富含螺旋束的复杂结构的细长分子。为了探索UL 37 N末端的功能，我们使用由结构提供的三维框架结合进化痕迹分析来确定几个具有潜在功能重要性的表面暴露区域，并使用诱变来测试它们的重要性。这种方法确定了一个新的功能区重要的细胞间传播。这些结果表明UL 37在细胞内病毒运输中的新作用，其促进病毒感染的传播，这一发现扩展了UL 37功能的库。支持这一点，UL 37的N末端与细胞多亚基拴系复合物（MTCs）共享结构相似性，MTCs通过将运输囊泡拴系到其目的膜来控制真核细胞中的囊泡运输。我们的研究结果表明，UL 37可能是第一个病毒MTC模拟物，并为UL 37对病毒运输的重要性提供了结构上的依据。我们认为，疱疹病毒可能已经增选了MTC功能的UL 37，使衣壳细胞质出芽的目的地，并进一步对细胞连接传播到附近的细胞。
In cells infected with herpesviruses, two capsid-associated, or inner tegument, proteins, UL37 and UL36, control cytosolic trafficking of capsids by as yet poorly understood mechanisms. Here, we report the crystal structure of the N-terminal half of UL37 from pseudorabies virus, an alphaherpesvirus closely related to herpes simplex viruses and varicella-zoster virus. The structure-the first for any alphaherpesvirus inner tegument protein-reveals an elongated molecule of a complex architecture rich in helical bundles. To explore the function of the UL37 N terminus, we used the three-dimensional framework provided by the structure in combination with evolutionary trace analysis to pinpoint several surface-exposed regions of potential functional importance and test their importance using mutagenesis. This approach identified a novel functional region important for cell-cell spread. These results suggest a novel role for UL37 in intracellular virus trafficking that promotes spread of viral infection, a finding that expands the repertoire of UL37 functions. Supporting this, the N terminus of UL37 shares structural similarity with cellular multisubunit tethering complexes (MTCs), which control vesicular trafficking in eukaryotic cells by tethering transport vesicles to their destination membranes. Our results suggest that UL37 could be the first viral MTC mimic and provide a structural rationale for the importance of UL37 for viral trafficking. We propose that herpesviruses may have co-opted the MTC functionality of UL37 to bring capsids to cytoplasmic budding destinations and further on to cell junctions for spread to nearby cells.