Structural Basis for Penetration of the Glycan Shield of Hepatitis C Virus E2 Glycoprotein by a Broadly Neutralizing Human Antibody [Protein Structure and Folding]

March 3rd, 2015 by Li, Y., Pierce, B. G., Wang, Q., Keck, Z.-Y., Fuerst, T. R., Foung, S. K. H., Mariuzza, R. A.

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 (E2412-423) have broadly neutralizing activities. However, an adaptive mutation in this linear epitope, Asn417Ser, is associated with a glycosylation shift from Asn417 to Asn415 that enables HCV to escape neutralization by monoclonal antibodies (mAbs) such as HCV1 and AP33. By contrast, the human mAb HC33.1 can neutralize virus bearing the Asn417Ser mutation. To understand how HC33.1 penetrates the glycan shield created by the glycosylation shift to Asn415, we determined the structure of this broadly neutralizing mAb in complex with its E2412-423 epitope to 2.0 Å resolution. The conformation of E2412-423 bound to HC33.1 is distinct from the β-hairpin conformation of this peptide bound to HCV1 or AP33, due to disruption of the β-hairpin through interactions with the unusually long complementarity-determining region 3 (CDR3) of the HC33.1 heavy chain. Whereas Asn415 is buried by HCV1 and AP33, it is solvent-exposed in the HC33.1-E2412-423 complex, such that glycosylation of Asn415 would not prevent antibody binding. Furthermore, our results highlight the structural flexibility of the E2412-423 epitope, which may serve as an immune evasion strategy to impede induction of antibodies targeting this site by reducing its antigenicity.
  • Posted in Journal of Biological Chemistry, Publications
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