Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108.
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11727-11734. doi: 10.1073/pnas.2003138117. Epub 2020 May 6.
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.
一种新型严重急性呼吸综合征(SARS)样冠状病毒(SARS-CoV-2)正在引发全球 2019 年冠状病毒病(COVID-19)大流行。了解 SARS-CoV-2 如何进入人体细胞是破解其奥秘和遏制其传播的当务之急。病毒表面刺突蛋白介导 SARS-CoV-2 进入细胞。为了发挥其功能,SARS-CoV-2 刺突通过其受体结合域(RBD)与人类 ACE2(hACE2)结合,并被人类蛋白酶进行蛋白水解激活。在这里,我们使用生化和假病毒进入测定法研究了 SARS-CoV-2 刺突的受体结合和蛋白酶激活。我们的研究结果确定了 SARS-CoV-2 的关键细胞进入机制。首先,SARS-CoV-2 RBD 与人 ACE2 的结合亲和力高于 SARS-CoV RBD,支持有效的细胞进入。其次,令人费解的是,整个 SARS-CoV-2 刺突与人 ACE2 的结合亲和力与 SARS-CoV 刺突相当或更低,这表明 SARS-CoV-2 RBD 虽然更有效,但比 SARS-CoV RBD 暴露得更少。第三,与 SARS-CoV 不同,SARS-CoV-2 的细胞进入是由前蛋白转化酶 furin 预激活的,从而降低了对靶细胞蛋白酶进入的依赖性。RBD 的高 hACE2 结合亲和力、刺突的 furin 预激活以及刺突中的隐藏 RBD 可能使 SARS-CoV-2 能够在逃避免疫监视的同时保持有效的细胞进入。这些特征可能有助于病毒的广泛传播。成功的干预策略必须针对 SARS-CoV-2 的效力及其逃避能力。
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