“Our study shows for the first time that the glycans are more than just a protective shield,” which is how they are typically thought of, Dr. Rommie E. Amaro of the University of California, San Diego, told Reuters Health by email. “We showed that some glycans can be both shield and part of the weaponry itself. They are able to become part of the weaponry by slipping underneath the receptor-binding domain (RBD) and propping up the RBD into the infectious conformation.”
The extensively glycosylated SARS-CoV-2 spike (S) protein mediates cell entry by binding to angiotensin-converting enzyme 2 (ACE2) on host cells. SARS-CoV-2 also uses its glycan shield to hide the spike protein from host immune responses.
Dr. Amaro and colleagues built a full-length model of the glycosylated SARS-CoV-2 S protein and used it to investigate the role of glycans in SARS-CoV-2 infectivity.
Two N-glycans (linked to N165 and N234) played an essential structural role in modulating conformational transitions of SARS-CoV-2’s RBD, which is responsible for ACE2 recognition.
Deletion of these glycans through mutations significantly reduced binding to ACE2 as a result of a conformational shift of RBD toward a “down” state, the researchers report in ACS Central Science.
They speculate that excising these glycans might result in less infectious or weakened viruses bearing S proteins with such predominantly “down” RBDs.
Additional studies found that 19 N-glycans camouflage the head region of the S protein, whereas the stalk bears only three glycosylation sites. Nevertheless, the stalk is almost completely inaccessible to such large molecules as antibodies, whereas the extensive glycan camouflaging of the head region still leaves 38% of its surface area exposed.
“Our study showed very clearly that the spike has to change conformations to ‘reveal’ the tip of the spike, which is like the arrowhead that’s needed to infect the cell (by interacting with ACE2),” Dr. Amaro said. “By changing the position of the RBD, the spike can sometimes be hidden (when the RBD is ‘down’) underneath the glycan shield, but then when the RBD adopts the ‘open’ conformation, it is propped above this shield and can infect the cell.”
“I hope people take away from our work that computational simulations have a unique role to play in fighting SARS-CoV-2,” she said. “By using computational simulations, we can get unseen views into the details of the virus that are currently intractable experimentally. Such understanding can help inform vaccine and therapeutic design, together with experiment.”
SOURCE: https://bit.ly/3674cI9 ACS Central Science, online September 23, 2020.
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