Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility
Abstract 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 Omic...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-84276-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559580802285568 |
|---|---|
| author | Jurij Froese Marco Mandalari Monica Civera Stefano Elli Isabel Pagani Elisa Vicenzi Itzel Garcia-Monge Daniele Di Iorio Saskia Frank Antonella Bisio Dominik Lenhart Rudolf Gruber Edwin A. Yates Ralf P. Richter Marco Guerrini Seraphine V. Wegner Kay Grobe |
| author_facet | Jurij Froese Marco Mandalari Monica Civera Stefano Elli Isabel Pagani Elisa Vicenzi Itzel Garcia-Monge Daniele Di Iorio Saskia Frank Antonella Bisio Dominik Lenhart Rudolf Gruber Edwin A. Yates Ralf P. Richter Marco Guerrini Seraphine V. Wegner Kay Grobe |
| author_sort | Jurij Froese |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-f282a36f17d0449199d91d7ac85ce975 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-f282a36f17d0449199d91d7ac85ce9752025-01-05T12:23:44ZengNature PortfolioScientific Reports2045-23222024-12-0114111610.1038/s41598-024-84276-5Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobilityJurij Froese0Marco Mandalari1Monica Civera2Stefano Elli3Isabel Pagani4Elisa Vicenzi5Itzel Garcia-Monge6Daniele Di Iorio7Saskia Frank8Antonella Bisio9Dominik Lenhart10Rudolf Gruber11Edwin A. Yates12Ralf P. Richter13Marco Guerrini14Seraphine V. Wegner15Kay Grobe16Institute of Physiological Chemistry and Pathobiochemistry, University of MünsterIstituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”Dipartimento di Chimica, Università degli Studi di MilanoIstituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”Viral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific InstituteViral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific InstituteSchool of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, University of LeedsInstitute of Physiological Chemistry and Pathobiochemistry, University of MünsterInstitute of Physiological Chemistry and Pathobiochemistry, University of MünsterIstituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”Bene PharmaChem GmbH and Co.KGBene PharmaChem GmbH and Co.KGDepartment of Biochemistry, Systems and Cell Biology, Institute of Molecular, Integrative and Systems Biology, University of LiverpoolSchool of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, University of LeedsIstituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”Institute of Physiological Chemistry and Pathobiochemistry, University of MünsterInstitute of Physiological Chemistry and Pathobiochemistry, University of MünsterAbstract 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.https://doi.org/10.1038/s41598-024-84276-5COVID-19SARS-CoV-2Heparan sulfateHeparinS-proteinIntersegmental transfer |
| spellingShingle | Jurij Froese Marco Mandalari Monica Civera Stefano Elli Isabel Pagani Elisa Vicenzi Itzel Garcia-Monge Daniele Di Iorio Saskia Frank Antonella Bisio Dominik Lenhart Rudolf Gruber Edwin A. Yates Ralf P. Richter Marco Guerrini Seraphine V. Wegner Kay Grobe Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility Scientific Reports COVID-19 SARS-CoV-2 Heparan sulfate Heparin S-protein Intersegmental transfer |
| title | Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility |
| title_full | Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility |
| title_fullStr | Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility |
| title_full_unstemmed | Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility |
| title_short | Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility |
| title_sort | evolution of sars cov 2 spike trimers towards optimized heparan sulfate cross linking and inter chain mobility |
| topic | COVID-19 SARS-CoV-2 Heparan sulfate Heparin S-protein Intersegmental transfer |
| url | https://doi.org/10.1038/s41598-024-84276-5 |
| work_keys_str_mv | AT jurijfroese evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT marcomandalari evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT monicacivera evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT stefanoelli evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT isabelpagani evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT elisavicenzi evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT itzelgarciamonge evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT danielediiorio evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT saskiafrank evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT antonellabisio evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT dominiklenhart evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT rudolfgruber evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT edwinayates evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT ralfprichter evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT marcoguerrini evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT seraphinevwegner evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility AT kaygrobe evolutionofsarscov2spiketrimerstowardsoptimizedheparansulfatecrosslinkingandinterchainmobility |