Structure of mouse coronavirus spike protein complexed with receptor reveals mechanism for viral entry
| Autor: | Guiqing Peng, Boyd Yount, Fang Li, Kendra Gully, Ashley Auerbach, Yushun Wan, Chang Liu, Yang Yang, Jian Shang, Ralph S. Baric |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Protein Conformation alpha-Helical Metabolic Processes RNA viruses Protein Conformation Physiology Coronaviruses viruses Action Potentials COVID-19 Viral entry Pattern recognition receptors Proteolysis Electron cryo-microscopy Proteases Recombination-based assay Serine proteases Plasma protein binding Pathology and Laboratory Medicine medicine.disease_cause Membrane Fusion Biochemistry Immune Receptors Mice Protein structure Medicine and Health Sciences Electron Microscopy Biology (General) Receptor Coronavirus Microscopy 0303 health sciences Immune System Proteins Chemistry 030302 biochemistry & molecular biology Recombinant Proteins Enzymes 3. Good health Cell biology Electrophysiology Severe acute respiratory syndrome-related coronavirus Medical Microbiology Viral Pathogens Spike Glycoprotein Coronavirus Viruses Receptors Virus Pathogens Protein Binding Research Article Signal Transduction Viral Entry QH301-705.5 Immunology Protein domain Virus Attachment Neurophysiology Research and Analysis Methods Membrane Potential Microbiology 03 medical and health sciences Protein Domains Cell Line Tumor Virology Genetics medicine Animals Humans Microbial Pathogens Molecular Biology 030304 developmental biology Murine hepatitis virus Cryoelectron Microscopy HEK 293 cells Organisms Biology and Life Sciences Proteins Lipid bilayer fusion Electron Cryo-Microscopy Cell Biology Virus Internalization RC581-607 Carcinoembryonic Antigen HEK293 Cells Metabolism Enzymology Parasitology Protein Multimerization Serine Proteases Immunologic diseases. Allergy Pattern Recognition Receptors Viral Transmission and Infection Neuroscience |
| Zdroj: | PLoS Pathogens, Vol 16, Iss 3, p e1008392 (2020) PLoS pathogens, 16(3):e1008392 PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Coronaviruses recognize a variety of receptors using different domains of their envelope-anchored spike protein. How these diverse receptor recognition patterns affect viral entry is unknown. Mouse hepatitis coronavirus (MHV) is the only known coronavirus that uses the N-terminal domain (NTD) of its spike to recognize a protein receptor, CEACAM1a. Here we determined the cryo-EM structure of MHV spike complexed with mouse CEACAM1a. The trimeric spike contains three receptor-binding S1 heads sitting on top of a trimeric membrane-fusion S2 stalk. Three receptor molecules bind to the sides of the spike trimer, where three NTDs are located. Receptor binding induces structural changes in the spike, weakening the interactions between S1 and S2. Using protease sensitivity and negative-stain EM analyses, we further showed that after protease treatment of the spike, receptor binding facilitated the dissociation of S1 from S2, allowing S2 to transition from pre-fusion to post-fusion conformation. Together these results reveal a new role of receptor binding in MHV entry: in addition to its well-characterized role in viral attachment to host cells, receptor binding also induces the conformational change of the spike and hence the fusion of viral and host membranes. Our study provides new mechanistic insight into coronavirus entry and highlights the diverse entry mechanisms used by different viruses. Author summary Coronaviruses recognize many receptors using their envelope-anchored spike protein. The role of receptor binding in coronavirus entry into host cells is a fundamental question in virology. Mouse hepatitis coronavirus (MHV) is unique among all coronaviruses in that it uses the N-terminal domain (NTD) of its spike protein to bind a protein receptor CEACAM1a. While extensive research has been performed on the cell entry mechanisms of coronaviruses that use a different domain of their spike protein for receptor binding, the cell entry mechanism for MHV is still elusive. Here we determined the cryo-EM structure of MHV spike protein complexed with CEACAM1a. The structure reveals unique features of receptor binding by MHV spike that facilitate the structural changes of MHV spike and promote cell entry of MHV. We further confirmed the structural results with biochemical and negative-stain EM analyses. These results suggest that receptor binding plays dual roles in MHV entry: it promotes both viral attachment to host cells and the fusion of host and viral membranes. Our study provides insight into the molecular mechanism of MHV entry, demonstrating how cell entry of MHV has been adapted to its unique way of receptor binding. |
| Databáze: | OpenAIRE |
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