OmniVira

Structural and functional analyses reveal promiscuous and species specific use of ephrin receptors by Cedar virus.

Eric D Laing1 Chanakha K Navaratnarajah2 Sofia Cheliout Da Silva1 Stephanie R Petzing1 Yan Xu3 Spencer L Sterling1 Glenn A Marsh4 Lin-Fa Wang5 Moushimi Amaya1 Dimitar B Nikolov3 Roberto Cattaneo2 Christopher C Broder6,7 Kai Xu8,7
Affiliations 8 institutions
  1. Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
  2. Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905.
  3. Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  4. Commonwealth Scientific and Industrial Research Organization Australian Animal Health Laboratory, Geelong, VIC 3219, Australia.
  5. Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857.
  6. Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
  7. [email protected] [email protected].
  8. Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065
PMID31548390 DOI10.1073/pnas.1911773116 Year2019 Journal Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A Languageeng Statusppublish

Abstract

Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.

Supporting text Virus Host Location
Cedar virus 2 entry 7 ephrins 2 henipaviruses 5 virus receptors 1 Animals 1948 Cell Fusion 6 Ephrin-B1 2 Ephrin-B2 14 Ephrin-B3 6 Henipavirus 18 Henipavirus Infections 65 Humans 1440 Mice 253 Mutation 209 Protein Binding 193 Protein Conformation 44 Receptors, Virus 204 Species Specificity 84 Viral Envelope Proteins 60 Virus Internalization 100 attachment protein G 8

Evidence records

2 total
Functional Mechanism
2 records · 1 evidence types
Evidence type Receptor Usage
2 records
OVE3444 Receptor Usage
Key finding

Cedar virus uses multiple ephrin receptors, including ephrin-B1, ephrin-A2, and ephrin-A5, in addition to ephrin-B2 for cell entry.

Virus
Cedar virus
Host
Not specified
Location
Not specified
Supporting text

Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2.

Method
cell entry assay | crystal structure determination | complex structure analysis
Receptors
ephrin-B1 | ephrin-A2 | ephrin-A5 | ephrin-B2
OVE3445 Receptor Usage
Key finding

Cedar virus can enter cells through mouse ephrin-A1 but not human ephrin-A1, indicating species-specific receptor usage determined by a single residue difference.

Virus
Cedar virus
Host
house mouse Mus musculus Experimental system human Homo sapiens Experimental system
Location
Not specified
Supporting text

We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region.

Method
cell entry assay | mutational comparison
Receptors
ephrin-A1