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Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses
Cheng-Bao Ma1, Chen Liu1, Young-Jun Park2
1State Key Laboratory of Virology and Biosafety, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, Hubei, China.
Abstract:
The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two bat MERS-related coronaviruses (MERSr-CoVs) infecting Pipistrellus nathusii (P.nat)-MOW15-22 and PnNL2018B-use ACE2 as their receptor, with narrow ortholog specificity. Cryoelectron microscopy structures of the MOW15-22/PnNL2018B RBD-ACE2 complexes unveil an unexpected and entirely distinct binding mode, mapping >45 Å away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble P.nat ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor.
Insights
Two bat coronaviruses utilize the ACE2 receptor through a novel binding mechanism, revealing diverse SARS-CoV-2 entry pathways and host tropism factors. This discovery highlights the adaptability of merbecoviruses.
Area of Science:
- Virology
- Structural Biology
- Mammalian Host-Pathogen Interactions
Background:
- The angiotensin-converting enzyme 2 (ACE2) receptor is a key entry point for various coronaviruses, including SARS-CoV-2.
- Understanding how different coronaviruses, particularly MERS-related coronaviruses (MERSr-CoVs), acquire ACE2 usage is crucial for predicting zoonotic spillover events.
Purpose of the Study:
- To investigate the ACE2 receptor usage and binding mechanisms of two MERSr-CoVs identified in Pipistrellus nathusii bats.
- To identify host tropism determinants and explore potential therapeutic strategies targeting ACE2-coronavirus interactions.
Main Methods:
- Cryoelectron microscopy was employed to determine the structures of MERSr-CoV RBD-ACE2 complexes.
- Functional profiling of ACE2 orthologs across 105 mammalian species was conducted.
- A soluble ACE2 mutant was designed for viral neutralization assays.
Main Results:
- Two bat MERSr-CoVs (MOW15-22 and PnNL2018B) were confirmed to use ACE2 as their receptor with narrow ortholog specificity.
- Cryo-EM structures revealed a distinct ACE2 binding mode, significantly different from other known ACE2-using coronaviruses.
- An N432-glycosylation site on ACE2 was identified as a key determinant restricting viral recognition, and a soluble P.nat ACE2 mutant demonstrated potent neutralizing activity.
Conclusions:
- Merbecoviruses in European bats have convergently acquired ACE2 usage through novel binding mechanisms.
- The ACE2 receptor exhibits remarkable promiscuity in binding diverse coronaviruses.
- These findings deepen our understanding of coronavirus evolution and host tropism, offering insights for pandemic preparedness.
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