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    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.   
      
      
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   FULL STORY   
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   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   
      
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