tetano
Editor, Senior Moderator
Chem Sci
. 2023 Jun 5;14(25):6997-7004.
doi: 10.1039/d2sc06967a. eCollection 2023 Jun 28. The ACE2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion
Marcos Cervantes[SUP] 1 [/SUP], Tobin Hess[SUP] 1 [/SUP], Giorgio G Morbioli[SUP] 1 [/SUP], Anjali Sengar[SUP] 1 [/SUP], Peter M Kasson[SUP] 1 2 [/SUP]
Affiliations
The SARS-CoV-2 coronavirus infects human cells via the ACE2 receptor. Structural evidence suggests that ACE2 may not just serve as an attachment factor but also conformationally activate the SARS-CoV-2 spike protein for membrane fusion. Here, we test that hypothesis directly, using DNA-lipid tethering as a synthetic attachment factor in place of ACE2. We find that SARS-CoV-2 pseudovirus and virus-like particles are capable of membrane fusion without ACE2 if activated with an appropriate protease. Thus, ACE2 is not biochemically required for SARS-CoV-2 membrane fusion. However, addition of soluble ACE2 speeds up the fusion reaction. On a per-spike level, ACE2 appears to promote activation for fusion and then subsequent inactivation if an appropriate protease is not present. Kinetic analysis suggests at least two rate-limiting steps for SARS-CoV-2 membrane fusion, one of which is ACE2 dependent and one of which is not. Since ACE2 serves as a high-affinity attachment factor on human cells, the possibility to replace it with other factors implies a flatter fitness landscape for host adaptation by SARS-CoV-2 and future related coronaviruses.
. 2023 Jun 5;14(25):6997-7004.
doi: 10.1039/d2sc06967a. eCollection 2023 Jun 28. The ACE2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion
Marcos Cervantes[SUP] 1 [/SUP], Tobin Hess[SUP] 1 [/SUP], Giorgio G Morbioli[SUP] 1 [/SUP], Anjali Sengar[SUP] 1 [/SUP], Peter M Kasson[SUP] 1 2 [/SUP]
Affiliations
- PMID: 37389252
- PMCID: PMC10306070
- DOI: 10.1039/d2sc06967a
The SARS-CoV-2 coronavirus infects human cells via the ACE2 receptor. Structural evidence suggests that ACE2 may not just serve as an attachment factor but also conformationally activate the SARS-CoV-2 spike protein for membrane fusion. Here, we test that hypothesis directly, using DNA-lipid tethering as a synthetic attachment factor in place of ACE2. We find that SARS-CoV-2 pseudovirus and virus-like particles are capable of membrane fusion without ACE2 if activated with an appropriate protease. Thus, ACE2 is not biochemically required for SARS-CoV-2 membrane fusion. However, addition of soluble ACE2 speeds up the fusion reaction. On a per-spike level, ACE2 appears to promote activation for fusion and then subsequent inactivation if an appropriate protease is not present. Kinetic analysis suggests at least two rate-limiting steps for SARS-CoV-2 membrane fusion, one of which is ACE2 dependent and one of which is not. Since ACE2 serves as a high-affinity attachment factor on human cells, the possibility to replace it with other factors implies a flatter fitness landscape for host adaptation by SARS-CoV-2 and future related coronaviruses.