A tighter core stabilizes SARS-CoV-2 spike protein in new emergent
variants
Mutations made spike protein more rigid, potentially improving virus's
fitness

Date:
March 31, 2023
Source:
Penn State
Summary:
New research reveals that mutations in the stem of the SARS-CoV-2
spike protein led to the virus becoming progressively tighter
over time, which may have improved the virus's ability to transmit
through nasal droplets and infect host cells once in the body.


Facebook Twitter Pinterest LinkedIN Email
FULL STORY ==========================================================================
Just as a tight core is a component of good physical fitness for humans, helping to stabilize our bodies, mutations that tightened the core of
the SARS- CoV-2 spike protein in new variants may have increased the
virus's fitness.


==========================================================================
New research led by Penn State reveals that the stem region of the spike protein became progressively tighter over time, and the team thinks this
likely improved the virus's ability to transmit through nasal droplets
and infect host cells once in the body. The team said the stem region of
the protein that emerged in the most recent Omicron variants is as rigid
as it can get, which could mean that newer vaccines may be effective
for longer than the ones that targeted the original variant.

"We wanted to see how the spike protein morphed structurally as it
evolved from the original wild-type strain of the virus, through the
alpha, delta and most recently Omicron variants," said Ganesh Anand,
associate professor of chemistry and of biochemistry and molecular
biology, Penn State. "We found that the spike protein was initially
more flexible at the stem region, which is where the spike protein is
bundled together, but over time, mutations caused the protein to become progressively tighter and more rigid, and we think it's now as rigid as
it can get. This is important because it means that vaccines that are
developed to target the current variant with these rigid spike proteins
are likely to be effective for much longer than previous vaccines against
the more flexible wild-type strain." To study how the spike protein
changed with each of the new variants, the team studied the virus in
vitro (in a test tube) using a technique called amide hydrogen/deuterium exchange mass spectrometry.

Anand explained that the SARS-CoV-2 spike protein is composed of
three chain molecules called monomers that are bound together to form
a trimer. The spike protein is made up of two subunits, an S1 and S2
subunit. The S1 subunit contains a receptor binding domain while the S2
subunit contains the stem region responsible for bundling the trimer.

"It is analogous to a tree, with the stem forming the trunk and the
receptor binding domain forming the branches," said Anand.

The team's results, which published in the journal eLife, revealed that
the spike protein stem first became more rigid with the D614G mutation,
which is common to all SARS-CoV-2 variants. The stem became progressively
more twisted with the emergence of new mutations in subsequent variants,
and the Omicron BA.1 variant showed the largest magnitude increase in stabilization relative to preceding variants.

Why would the virus benefit from a tighter core? "We did not study the
virus in patients, so we cannot determine if the changes we observed
in the spike protein directly affected the newer variants such as
Omicron's ability to transmit more readily; however, we can say that
the changes likely made the virus more fit, which could translate to
better transmission," said Anand. "A tighter core could likely make
the virus more stable in nasal droplets and faster at binding to and
entering host cells. So, for example, what initially took about 11 days
to develop an infection after exposure now takes only about four days."
Anand noted that one of the reasons the vaccines have not been able to
fully neutralize the virus is because they were generated against the
spike protein of the original wild-type variant.

"The latest bivalent booster -- which targets newer variants -- helps,
but people who never got this booster aren't receiving this more targeted protection," he said. "Future vaccines that focus specifically on Omicron
are likely to be effective for longer." Finally, Anand said that the
spike protein has now become so tightly twisted that it is unlikely to structurally change further at the stem region.

"There are limits to how much it can tighten," he said. "I think
that we can have some cautious optimism, in that we're not going to continuously have variants emerging, at least tightening is not going
to be a mechanism." Other Penn State authors on the paper include
chemistry graduate students Sean Braet, Theresa Buckley and Varun Venkatakrishnan. Kim-Marie Dam, postdoctoral research fellow, and Pamela Bjorkman, assistant professor of biology and biological engineering,
Caltech, also are authors.

* RELATED_TOPICS
o Health_&_Medicine
# HIV_and_AIDS # Stem_Cells # Human_Biology # Viruses #
Infectious_Diseases # Vaccines # Nervous_System # Herpes
* RELATED_TERMS
o Virus o Severe_acute_respiratory_syndrome o Adult_stem_cell
o Nasal_congestion o Embryonic_stem_cell o Rubella o
West_Nile_virus o Stem_cell

========================================================================== Story Source: Materials provided by Penn_State. Original written by Sara LaJeunesse. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Varun Venkatakrishnan, Theresa SC Buckley, Sean M Braet, Kim-Marie
A Dam,
Pamela J Bjorkman, Ganesh S Anand. Timeline of changes in spike
conformational dynamics in emergent SARS-CoV-2 variants reveal
progressive stabilization of trimer stalk with altered NTD dynamics.

eLife, 2023; 12 DOI: 10.7554/eLife.82584 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/03/230331131453.htm

--- up 1 year, 4 weeks, 4 days, 10 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)