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Literature detail

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2.

Thomas Mandel Clausen1,2,3 Daniel R Sandoval4 Charlotte B Spliid1,2,5 Jessica Pihl1,2,5 Hailee R Perrett6 Chelsea D Painter1,7 Anoop Narayanan8 Sydney A Majowicz8 Elizabeth M Kwong9 Rachael N McVicar9 Bryan E Thacker10 Charles A Glass10 Zhang Yang11 Jonathan L Torres6 Gregory J Golden1,7 Phillip L Bartels1,12 Ryan N Porell13 Aaron F Garretson14 Logan Laubach13 Jared Feldman15 Xin Yin16 Yuan Pu16 Blake M Hauser15 Timothy M Caradonna15 Benjamin P Kellman17,18,19 Cameron Martino17,20 Philip L S M Gordts21,12 Sumit K Chanda16 Aaron G Schmidt22,23 Kamil Godula24,12 Sandra L Leibel20 Joyce Jose8 Kevin D Corbett4 Andrew B Ward6 Aaron F Carlin14 Jeffrey D Esko1,25
Affiliations 25 institutions
  1. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
  2. Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
  3. Department of Infectious Disease, Copenhagen University Hospital, 2200 Copenhagen, Denmark. Electronic address: [email protected].
  4. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  5. Department of Infectious Disease, Copenhagen University Hospital, 2200 Copenhagen, Denmark.
  6. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  7. Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA.
  8. Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
  9. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  10. TEGA Therapeutics, Inc., 3550 General Atomics Court, G02-102, San Diego, CA 92121, USA.
  11. Copenhagen Center for Glycomics, Department of Molecular and Cellular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
  12. Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
  13. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  14. Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
  15. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
  16. Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  17. Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
  18. Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
  19. Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
  20. Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
  21. Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA
  22. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
  23. Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
  24. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
  25. Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
PMID 32970989 2020 Cell eng ppublish
PubMed DOI Browse context

Article

Publication summary

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

coronavirus COVID-19 heparan sulfate heparan sulfate-binding proteins heparin lung epithelial cells pseudotyped virus SARS-CoV-2 spike proteins Amino Acid Sequence Angiotensin-Converting Enzyme 2 Betacoronavirus Binding Sites Cell Line Coronavirus Infections COVID-19 Heparan Sulfate Heparin

Structured evidence records

Evidence records

2 total
Receptor Usage 2 records
Receptor Usage Extraction confidence 1.00
Key finding

SARS-CoV-2 spike protein binds both heparan sulfate and ACE2 via its receptor-binding domain, indicating dual receptor involvement in viral entry.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD).

Method
binding assay; electron microscopy; pseudovirus assay; molecular docking
Receptors
ACE2
Host factors
heparan sulfate
Receptor Usage Extraction confidence 1.00
Key finding

Cellular heparan sulfate mediates SARS-CoV-2 spike protein attachment and enhances ACE2-dependent infection; exogenous heparin blocks viral binding and entry.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus.

Method
pseudovirus assay; binding assay; infection assay
Receptors
heparan sulfate
Host factors
ACE2