期刊
JOURNAL OF VIROLOGY
卷 85, 期 2, 页码 865-872出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01412-10
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资金
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [HHSN266200700005C]
- Cancer Center [CA21765]
- American Lebanese Syrian Associated Charities (ALSAC)
- Children's Infection Defense Center (CIDC) at St. Jude Children's Research Hospital
- FEMSA
- Tecnologico de Monterrey [CAT-122]
- Department of Energy, Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences
- Zambrano-Hellion family
- NATIONAL CANCER INSTITUTE [P30CA021765] Funding Source: NIH RePORTER
The hemagglutinin (HA) surface glycoprotein promotes influenza virus entry and is the key protective antigen in natural immunity and vaccines. The HA protein is a trimeric envelope glycoprotein consisting of a globular receptor-binding domain (HA-RBD) that is inserted into a membrane fusion-mediating stalk domain. Similar to other class I viral fusion proteins, the fusogenic stalk domain spontaneously refolds into its postfusion conformation when expressed in isolation, consistent with this domain being trapped in a metastable conformation. Using X-ray crystallography, we show that the influenza virus HA-RBD refolds spontaneously into its native, immunogenic structure even when expressed in an unglycosylated form in Escherichia coli. In the 2.10-angstrom structure of the HA-RBD, the receptor-binding pocket is intact and its conformational epitopes are preserved. Recombinant HA-RBD is immunogenic and protective in ferrets, and the protein also binds with specificity to sera from influenza virus-infected humans. Overall, the data provide a structural basis for the rapid production of influenza vaccines in E. coli. From an evolutionary standpoint, the ability of the HA-RBD to refold spontaneously into its native conformation suggests that influenza virus acquired this domain as an insertion into an ancestral membrane-fusion domain. The insertion of independently folding domains into fusogenic stalk domains may be a common feature of class I viral fusion proteins.
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