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.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
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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