Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility

The heparan sulfate (HS)-rich extracellular matrix (ECM) serves as an initial interaction site for the homotrimeric spike (S) protein of SARS-CoV-2 to facilitate subsequent docking to angiotensin-converting enzyme 2 (ACE2) receptors and cellular infection. More recent variants, notably Omicron, have...

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Published in:Scientific reports Vol. 14; no. 1; pp. 32174 - 16
Main Authors: Froese, Jurij, Mandalari, Marco, Civera, Monica, Elli, Stefano, Pagani, Isabel, Vicenzi, Elisa, Garcia-Monge, Itzel, Di Iorio, Daniele, Frank, Saskia, Bisio, Antonella, Lenhart, Dominik, Gruber, Rudolf, Yates, Edwin A., Richter, Ralf P., Guerrini, Marco, Wegner, Seraphine V., Grobe, Kay
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 31.12.2024
Nature Publishing Group
Nature Portfolio
Subjects:
631/114
631/154
631/45
631/57
692/699
ACE2
Amino acids
Angiotensin
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - chemistry
Angiotensin-Converting Enzyme 2 - metabolism
Cell migration
Cell surface
COVID-19
COVID-19 - metabolism
COVID-19 - virology
Enzymes
Evolution
Evolution, Molecular
Extracellular matrix
Extracellular Matrix - metabolism
Heparan sulfate
Heparin
Heparitin Sulfate - chemistry
Heparitin Sulfate - metabolism
Humanities and Social Sciences
Humans
Infections
Intersegmental transfer
Mobility
multidisciplinary
Peptidyl-dipeptidase A
Protein Binding
Protein Multimerization
Proteins
Receptor mechanisms
S-protein
SARS-CoV-2
SARS-CoV-2 - metabolism
Science
Science (multidisciplinary)
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - chemistry
Spike Glycoprotein, Coronavirus - genetics
Spike Glycoprotein, Coronavirus - metabolism
Sulfates
Trimers
COVID-19
Heparan sulfate
S-protein
SARS-CoV-2
Intersegmental transfer
Heparin
ISSN:2045-2322, 2045-2322
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Summary:The heparan sulfate (HS)-rich extracellular matrix (ECM) serves as an initial interaction site for the homotrimeric spike (S) protein of SARS-CoV-2 to facilitate subsequent docking to angiotensin-converting enzyme 2 (ACE2) receptors and cellular infection. More recent variants, notably Omicron, have evolved by swapping several amino acids to positively charged residues to enhance the interaction of the S-protein trimer with the negatively charged HS. However, these enhanced interactions may reduce Omicron’s ability to move through the HS-rich ECM to effectively find ACE2 receptors and infect cells, raising the question of how to mechanistically explain HS-associated viral movement. In this work, we show that Omicron S proteins have evolved to balance HS interaction stability and dynamics, resulting in enhanced mobility on an HS-functionalized artificial matrix. This property is achieved by the ability of Omicron S-proteins to cross-link at least two HS chains, allowing direct S-protein switching between chains as a prerequisite for cell surface mobility. Optimized HS interactions can be targeted pharmaceutically, as an HS mimetic significantly suppressed surface binding and cellular infection specifically of the Omicron variant. These findings suggest a robust way to interfere with SARS-CoV-2 Omicron infection and potentially future variants.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-024-84276-5