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Structural basis for penetration of the glycan shield of hepatitis C virus E2 glycoprotein by a broadly neutralizing human antibody.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2015 Apr 17; Vol. 290 (16), pp. 10117-25. Date of Electronic Publication: 2015 Mar 03. - Publication Year :
- 2015
-
Abstract
- Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. A challenge for HCV vaccine development is to identify conserved epitopes able to elicit protective antibodies against this highly diverse virus. Glycan shielding is a mechanism by which HCV masks such epitopes on its E2 envelope glycoprotein. Antibodies to the E2 region comprising residues 412-423 (E2(412-423)) have broadly neutralizing activities. However, an adaptive mutation in this linear epitope, N417S, is associated with a glycosylation shift from Asn-417 to Asn-415 that enables HCV to escape neutralization by mAbs such as HCV1 and AP33. By contrast, the human mAb HC33.1 can neutralize virus bearing the N417S mutation. To understand how HC33.1 penetrates the glycan shield created by the glycosylation shift to Asn-415, we determined the structure of this broadly neutralizing mAb in complex with its E2(412-423) epitope to 2.0 Å resolution. The conformation of E2(412-423) bound to HC33.1 is distinct from the β-hairpin conformation of this peptide bound to HCV1 or AP33, because of disruption of the β-hairpin through interactions with the unusually long complementarity-determining region 3 of the HC33.1 heavy chain. Whereas Asn-415 is buried by HCV1 and AP33, it is solvent-exposed in the HC33.1-E2(412-423) complex, such that glycosylation of Asn-415 would not prevent antibody binding. Furthermore, our results highlight the structural flexibility of the E2(412-423) epitope, which may serve as an immune evasion strategy to impede induction of antibodies targeting this site by reducing its antigenicity.<br /> (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Antibodies, Neutralizing genetics
Antibodies, Neutralizing immunology
Antigen-Antibody Complex genetics
Antigen-Antibody Complex immunology
Complementarity Determining Regions genetics
Complementarity Determining Regions immunology
Crystallography, X-Ray
Epitopes genetics
Epitopes immunology
Gene Expression Regulation, Viral immunology
Glycosylation
Hepacivirus immunology
Hepatitis C Antigens genetics
Hepatitis C Antigens immunology
Humans
Immune Evasion
Models, Molecular
Polysaccharides chemistry
Polysaccharides immunology
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins immunology
Viral Envelope Proteins genetics
Viral Envelope Proteins immunology
Antibodies, Neutralizing chemistry
Antigen-Antibody Complex chemistry
Complementarity Determining Regions chemistry
Epitopes chemistry
Hepacivirus genetics
Hepatitis C Antigens chemistry
Viral Envelope Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 290
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25737449
- Full Text :
- https://doi.org/10.1074/jbc.M115.643528