Single-molecule imaging reveals how SARS-CoV-2 binds to ACE2 receptors

The efficient spread of the SARS-CoV-2 coronavirus has been a subject of investigation and speculation among scientists. Researchers from the Julius Maximilians University of Würzburg have made new discoveries shedding light on this .

Contrary to previous assumptions, the virus does not bind simultaneously to multiple surface and multiple receptors on the target cell. Instead, the research team led by Dr. Simone Backes, Dr. Gerti Beliu, and Prof. Dr. Markus Sauer has provided evidence that a single virus binds to a single receptor, leading to highly efficient infection.

The spike proteins on the surface of SARS-CoV-2 play a crucial role in binding to ACE2 receptors in the target cell's membrane. The researchers found that when these receptors are blocked with antibodies, the cell becomes resistant to infection. This indicates that the binding of the virus to the ACE2 receptor is a crucial step in the infection process.

Until now, visualizing the ACE2 receptors and their interaction with viral spike proteins has been challenging. Speculations were made about whether the virus binds to multiple receptors or forms groups of receptors to enhance cell entry.

To solve this mystery, the Würzburg researchers used labeled antibodies and a super-resolution microscopy method called dSTORM. They examined various cell lines used as models for SARS-CoV infection and found that like Vero cells, commonly used for SARS-CoV-2 research, have only one to two ACE2 receptors per square micrometer of cell membrane. This number is remarkably low compared to other membrane receptors.

Moreover, the distance between neighboring ACE2 receptors is much larger than the size of a virus , making it unlikely for a virus with multiple spike proteins to bind to multiple receptors simultaneously.

These findings challenge previous assumptions about the binding mechanism of SARS-CoV-2 and provide new insights into the efficient spread of the virus. The research conducted by the Würzburg team contributes to our understanding of the infection process and may have implications for the development of effective therapeutic strategies.

ACE2 receptors are always single

Contrary to previous hypotheses, the ACE2 receptors in the cell membrane are present singly and not as pairs or groups of three, according to Beliu, a group leader at the Rudolf Virchow Center. Even after a viral spike has bound to them, the receptors remain singular. It has been established that a single spike binding to a single receptor is sufficient for infection.

The findings of the research team at JMU have debunked several initial assumptions about the interaction between viral particles and multiple ACE2 receptors. They have also demonstrated that cells expressing higher levels of ACE2 are more susceptible to infection, as expected. However, other factors such as the lipid composition of the membrane also influence the infection process.

To gain comprehensive knowledge about the mechanism by which coronaviruses enter cells and to enhance our understanding of the infection process, the JMU team aims to conduct further investigations. The ultimate goal is to contribute to better prevention and the development of more effective drugs against . The next step for the Würzburg researchers is to analyze the entry mechanism using high-resolution light sheet microscopy.

Source: Rudolf-Virchow-Zentrum

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