Coronaviruses use monomeric ACE2 molecules as entry receptors on host cells
For over three years, SARS-CoV-2, the pathogen that causes the respiratory disease known as COVID-19 or simply "corona", has been keeping us on our toes due to its high infectiousness and frequently severe, potentially deadly, clinical outcomes. How does the infection mechanism work on a molecular level? A research team from Würzburg (Germany) has now revealed new insights in the journal Angewandte Chemie.
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The surfaces of SARS-CoV-2 viruses are covered in 24 to 40 protruding spikes consisting of trimers made of three identical proteins. After over two years of research, it is undisputed that the critical first step of an infection is the binding of these spikes to the angiotensin-converting enzyme 2 (ACE2). ACE2 is present almost everywhere in the body and is involved in diverse physiological functions, such as the regulation of blood pressure and circulation. ACE2 acts as an entry receptor for the viruses. After binding, the virus particle invades the cell. Some questions have thus far remained unanswered: Do the spikes, which consist of three subunits, simultaneously bind to multiple ACE2 receptors? If they do, is ACE2 already present as a dimer or oligomer in the membrane? Or do several ACE2 molecules aggregate as a result of binding to the spikes? A team headed by Gerti Beliu and Markus Sauer now says that neither is the case.
The team at the University of Würzburg (Germany) labeled the ACE2 receptors of various cell lines that are used as models for COVID infection with various techniques involving fluorescence dyes and studied them with dSTORM (direct stochastic optical reconstruction microscopy). This fluorescence imaging method has extremely high resolution, beyond the diffraction limit of classic methods. In this way they were able to determine the number and distribution of the ACE2 receptors in the plasma membrane. It was shown that they are evenly distributed-as monomers-with a density of about one to two ACE2 molecules per square micrometer, which is low in comparison to most other membrane receptors. Studies after addition of trimeric viral spikes showed unambiguously that binding of these does not induce any formation of ACE2 dimers or oligomers.
Infection studies using another type of virus (vesicular stomatitis virus, VSV) that also has spikes, supported the conclusion that a single interaction between one single spike protein per virus particle with a single monomeric ACE2 receptor is enough to cause infection-likely one reason for the high infectiousness of SARS-CoV-2.
This new quantitative molecular information about the interactions between spike proteins and ACE2 on the cell membrane could offer new perspectives for the development of improved drugs for treating COVID infections.
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About the Author
Dr. Markus Sauer is the Professor of Biotechnology and Biophysics at the Biocenter of the University of Würzburg, as well as RV Professor at the Rudolf Virchow Center (RVZ) - Centre for Integrative and Translational Bioimaging. His research group works in the area of single-molecule fluorescence spectroscopy and the development of new high-resolution fluorescence imaging techniques for the efficient labeling of biomolecules. Dr. Gerti Beliu is leader of a research group at the RVZ working on the development of molecular probes for high-resolution fluorescence microscopy and the extension of the genetic code.
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