Functional Pangenome Analysis Shows Key Features of E Protein Are Preserved in SARS and SARS-CoV-2
Functional Pangenome Analysis Shows Key Features of E Protein Are Preserved in SARS and SARS-CoV-2
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DOI：
10.3389/fcimb.2020.00405
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发表时间：
2020-07-27
影响因子：
5.7
通讯作者：
Duarte, Carlos M.
中科院分区：
文献类型：
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作者：
Alam, Intikhab;Kamau, Allan A.;Duarte, Carlos M.
新型冠状病毒（SARS-CoV-2）的传播引发了全球紧急情况，需要紧急解决检测和治疗方案，以防止对健康、社会和经济的影响不断升级。该病毒的刺突蛋白(S)能够与人类受体ACE2结合，因此是预防病毒进入宿主细胞的疫苗的主要靶点。SARS和SARS- cov -2的S蛋白相似，但受体结合域（RBD）的结构差异阻碍了使用SARS特异性中和抗体来抑制SARS- cov -2。在这里，我们对所有测序的参比冠状病毒进行了比较全基因组分析，并辅以功能和结构分析。分析结果表明，在这些病毒中存在的所有核心基因簇中，包膜蛋白E显示出SARS和SARS- cov -2共有的变异簇，具有两个完全保守的关键功能特征，即离子通道和pdz结合基元（PBM）。这些特征在炎症小体的激活中发挥关键作用，导致急性呼吸窘迫综合征，这是SARS和SARS- cov -2感染的主要死亡原因。结合功能性全基因组分析、突变追踪和既往证据，我们建议E蛋白作为SARS致病性的决定因素，可作为进一步研究的替代治疗靶点，以减少COVID-19中SARS- cov -2感染的并发症。
The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social, and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells. The S proteins from SARS and SARS-CoV-2 are similar, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-specific neutralizing antibodies to inhibit SARS-CoV-2. Here we used comparative pangenomic analysis of all sequenced referenceBetacoronaviruses, complemented with functional and structural analyses. This analysis reveals that, among all core gene clusters present in these viruses, the envelope protein E shows a variant cluster shared by SARS and SARS-CoV-2 with two completely-conserved key functional features, namely an ion-channel, and a PDZ-binding motif (PBM). These features play a key role in the activation of the inflammasome causing the acute respiratory distress syndrome, the leading cause of death in SARS and SARS-CoV-2 infections. Together with functional pangenomic analysis, mutation tracking, and previous evidence, on E protein as a determinant of pathogenicity in SARS, we suggest E protein as an alternative therapeutic target to be considered for further studies to reduce complications of SARS-CoV-2 infections in COVID-19.