Seneca Valley virus attachment and uncoating mediated by its receptor anthrax toxin receptor 1
Seneca Valley virus attachment and uncoating mediated by its receptor anthrax toxin receptor 1
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塞内卡谷病毒由其受体炭疽毒素受体1介导的附着和脱壳
DOI：
10.1073/pnas.1814309115
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发表时间：
2018-12-18
影响因子：
11.1
通讯作者：
Rao, Zihe
中科院分区：
文献类型：
--
作者：
Cao, Lin;Zhang, Ran;Rao, Zihe
Seneca Valley病毒（SVV）选择性感染和裂解神经内分泌癌细胞，包括小细胞肺癌（SCLC）和儿科神经内分泌实体瘤，这是发病率和死亡率的主要原因。它正在临床试验中作为针对这些肿瘤的溶瘤剂进行开发。事实上，临床前和早期临床试验已经证实了SVV作为癌症治疗的安全性和有效性。我们确定了SVV-ANTXR 1在不同条件下的原子结构。一个最有吸引力的发现是，在界面上的VP 2 177位置处的丝氨酸至丙氨酸突变显著增加增殖。这项工作中显示的SVV-ANTXR 1附着和未包被的分子细节为优化SVV作为具有更高功效和更低免疫原性的溶瘤试剂提供了线索。Seneca Valley病毒（SVV）是一种选择性嗜神经内分泌癌的溶瘤小核糖核酸病毒。SVV通过附着于受体炭疽毒素受体1（ANTXR 1）介导细胞进入。在这里，我们确定成熟的SVV颗粒单独和复杂的ANTXR 1在中性和酸性条件下，以及空的“废”颗粒在复杂的ANTXR 1在酸性条件下，通过冷冻电子显微镜的原子结构。SVV主要通过VP 2 DF和VP 1 CD环与ANTXR 1结合，导致VP 1 GH环和VP 3 GH环的结构变化，这减弱了原聚体间的相互作用并使衣壳组装不稳定。尽管位于附着位点的边缘，但VP 2 D146与ANTXR 1中的金属离子相互作用，并且是细胞进入所需的。尽管大多数相互作用残基的单个取代废除了受体结合和病毒繁殖，但VP 2 S177处的丝氨酸至丙氨酸突变显著增加了SVV增殖。SVV-ANTXR 1复合物的酸化导致五聚体衣壳组件的主要重构，其围绕二十面体五重轴旋转约20°以形成先前未表征的废颗粒，其类似于在两重和三重轴处具有显著穿孔的潜在未包衣中间体。这些结构提供了SVV进入的高分辨率快照，突出了抗癌治疗优化的机会。
Significance Seneca Valley virus (SVV) selectively infects and lyses neuroendocrine cancer cells, including small-cell lung cancer (SCLC) and pediatric neuroendocrine solid tumors, which are a major cause of morbidity and mortality. It is under development in clinical trials as an oncolytic agent against these tumors. Indeed preclinical and early-phase clinical trials have confirmed the safety and efficacy of SVV as a cancer treatment. We determine the atomic structures for SVV–ANTXR1 in different conditions. A most attractive finding is that a serine-to-alanine mutation at VP2 177 position on the interface significantly increases proliferation. The molecular details for SVV–ANTXR1 attachment and uncoating shown in this work provide clues to optimize SVV as an oncolytic reagent with higher efficacy and lower immunogenicity. Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. SVV mediates cell entry by attachment to the receptor anthrax toxin receptor 1 (ANTXR1). Here we determine atomic structures of mature SVV particles alone and in complex with ANTXR1 in both neutral and acidic conditions, as well as empty “spent” particles in complex with ANTXR1 in acidic conditions by cryoelectron microscopy. SVV engages ANTXR1 mainly by the VP2 DF and VP1 CD loops, leading to structural changes in the VP1 GH loop and VP3 GH loop, which attenuate interprotomer interactions and destabilize the capsid assembly. Despite lying on the edge of the attachment site, VP2 D146 interacts with the metal ion in ANTXR1 and is required for cell entry. Though the individual substitution of most interacting residues abolishes receptor binding and virus propagation, a serine-to-alanine mutation at VP2 S177 significantly increases SVV proliferation. Acidification of the SVV–ANTXR1 complex results in a major reconfiguration of the pentameric capsid assemblies, which rotate ∼20° around the icosahedral fivefold axes to form a previously uncharacterized spent particle resembling a potential uncoating intermediate with remarkable perforations at both two- and threefold axes. These structures provide high-resolution snapshots of SVV entry, highlighting opportunities for anticancer therapeutic optimization.