ACE2 is also the receptor for alphacoronavirus HCoV-NL63, which, together with another alphacoronavirus, HCoV-229E, and betacoronaviruses HCoV-OC43 and HCoV-HKU1, is a known causative agent of mild upper respiratory tract infections 8. SARS-CoV-2 relies on its obligate receptor, angiotensin-converting enzyme 2 (ACE2), to enter cells 2, 3, 4, 5, 6 ACE2 was originally identified in 2003 as the receptor for SARS-CoV 7. 1), the genus also includes human coronavirus (HCoV)-OC43, HCoV-HKU1 and Middle East respiratory syndrome coronavirus (MERS-CoV). In addition to SARS-CoV, which was responsible for the 2002–2004 SARS epidemic and which shares 79% nucleotide sequence identity with SARS-CoV-2 (ref.
SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus of the genus Betacoronavirus 1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, which escalated into a global pandemic in 2020. Finally, we present key outstanding questions associated with this critical process. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion.
Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response.
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