The COVID-19 pandemic has prompted considerable investigation into how the SARS-CoV-2 Spike protein attaches to a human cell during the infection process, as this knowledge is useful in designing vaccines and therapeutics. Now, a team of scientists has discovered additional locations on the Spike protein that may not only help to explain how certain mutations make emerging variants more infectious but also could be used as additional targets for therapeutic intervention.
“Significant research is underway to examine how the receptor binding domain (RBD) at the tip of the club-shaped SARS-CoV-2 Spike protein attaches to an ACE2 receptor on a human cell, but little is known about the other changes that occur in the Spike protein as a result of this attachment,” said Ganesh Anand, associate professor of chemistry, Penn State. “We have uncovered ‘hotspots’ further down on the Spike protein that are critical for SARS-CoV-2 infection and may be novel targets beyond the RBD for therapeutic intervention.”
Anand and his colleagues used a process, called amide hydrogen-deuterium exchange mass spectrometry (HDXMS), to visualize what happens when the SARS-CoV-2 Spike protein binds to an ACE2 receptor. HDXMS uses heavy water or deuterium oxide (D2O), a naturally occurring, non-radioactive isotope of water formed from heavy hydrogen or deuterium, as a probe for mapping proteins. In this case, the team placed SARS-CoV-2 Spike protein and ACE2 receptors in heavy water and obtained footprints of ACE2 on the Spike protein.
“If you put the Spike protein and ACE2 receptor into a solution that’s made with D2O, the surfaces and more floppy regions on both proteins will more readily exchange hydrogens for deuterium, compared to their interiors,” said Anand. “And footprints of each protein on the binding partner can be readily identified from areas where you see little deuterium and only detect normal hydrogen.”
Using this technique, the team determined that binding of the Spike protein and ACE2 receptor is necessary for furin-like proteases—a family of human enzymes—that act to snip off the tip, called the S1 subunit, of the Spike protein, which is the next step in the virus’s infection of the cell. The findings published on Feb. 8 in the journal eLife.
Image Credit: NIH/NIAID
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