The crystal structure of vaccinia virus protein E2 and perspectives on the prediction of novel viral protein folds
The crystal structure of vaccinia virus protein E2 and perspectives on the prediction of novel viral protein folds
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DOI：
10.1101/2021.10.14.464338
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
W. Gao;Chen Gao;J. Deane;D. Carpentier;Geoffrey L. Smith;S. C. Graham
中科院分区：
文献类型：
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作者：
W. Gao;Chen Gao;J. Deane;D. Carpentier;Geoffrey L. Smith;S. C. Graham
牛痘病毒（痘病毒科）的形态发生是一个复杂的过程，涉及多个不同的细胞膜，并产生多种不同形式的传染性病毒粒子。有效释放包膜病毒粒子，促进感染在宿主内的全身传播，需要疫苗病毒蛋白E2，但E2功能的分子基础尚不清楚，E2缺乏与任何已知的蛋白家族的序列同源性。我们将VACV E2的晶体结构求解到2.3 Å分辨率，发现它包含两个具有新颖褶皱的结构域：n端环状结构域和c端头结构域。c端头部结构域与细胞（伪）激酶表现出较弱的结构同源性，但缺乏保守的表面残基或激酶特征，表明它不具有酶活性，并且具有可能与磷酸肌苷脂质头基相互作用的大表面碱性斑块。最近的深度学习方法已经彻底改变了我们仅从初级序列预测蛋白质三维结构的能力。VACV E2是一个典型的“困难”的病毒蛋白结构预测靶标，它由多个新的结构域组成，并且在痘病毒科外缺乏序列同源物。尽管如此，AlphaFold2还是成功地预测了头部和环状结构域的结构，分别具有较高和中等的精度，从而可以准确推断多种结构特性。高度精确的病毒结构预测的出现标志着结构病毒学的一个重大变化，预示着结构知识分子病毒学的新时代的到来。
The morphogenesis of vaccinia virus (VACV, family Poxviridae), the smallpox vaccine, is a complex process involving multiple distinct cellular membranes and resulting in multiple different forms of infectious virion. Efficient release of enveloped virions, which promote systemic spread of infection within hosts, requires the VACV protein E2 but the molecular basis of E2 function remains unclear and E2 lacks sequence homology to any well-characterised family of proteins. We solved the crystal structure of VACV E2 to 2.3 Å resolution, revealing that it comprises two domains with novel folds: an N-terminal annular (ring) domain and a C-terminal head domain. The C-terminal head domain displays weak structural homology with cellular (pseudo)kinases but lacks conserved surface residues or kinase features, suggesting that it is not enzymatically active, and possesses a large surface basic patch that might interact with phosphoinositide lipid headgroups. Recent deep learning methods have revolutionised our ability to predict the three-dimensional structures of proteins from primary sequence alone. VACV E2 is an exemplar ‘difficult’ viral protein target for structure prediction, being comprised of multiple novel domains and lacking sequence homologues outside Poxviridae. AlphaFold2 nonetheless succeeds in predicting the structures of the head and ring domains with high and moderate accuracy, respectively, allowing accurate inference of multiple structural properties. The advent of highly accurate virus structure prediction marks a step-change in structural virology and beckons a new era of structurally-informed molecular virology.