The human chorionic gonadotropin-ß arginine68 to glutamic acid substitution fixes the conformation of the C-terminal Peptide

Charrel-Dennis, Marie and Terrazzini, Nadia and McBride, Jeffrey D. and Martensen, Pia M. and Justesen, Just and Berger, Peter and Lapthorn, Adrian J. and Kelly, Charles and Roitt, Ivan and Delves, Peter J. and Lund, Torben (2005) The human chorionic gonadotropin-ß arginine68 to glutamic acid substitution fixes the conformation of the C-terminal Peptide. Molecular Endocrinology, 19 (7). pp. 1803-1811. ISSN 0888-8809

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Wild-type human chorionic gonadotropin (hCG) has been used as a contraceptive vaccine. However, extensive sequence homology with LH elicits production of cross-reactive antibodies. Substitution of arginine68 of the ß-subunit (hCGß) with glutamic acid (R68E) profoundly reduces the cross-reactivity while refocusing the immune response to the hCGß-specific C-terminal peptide (CTP). To investigate the molecular basis for this change in epitope usage, we immunized mice with a plasmid encoding a truncated hCGß-R68E chain lacking the CTP. The animals produced LH-cross-reactive antibodies, suggesting that the refocused immunogenicity of R68E is a consequence of epitope masking by a novel disposition of the CTP in the mutant rather than a structural change in the cross-reactive epitope region. This explanation was strongly supported by surface plasmon resonance analysis using a panel of anti-hCGß-specific and anti-hCGß/LH cross-reactive monoclonal antibodies (mAbs). Whereas the binding of the LH cross-reactive mAbs to hCGß-R68E was eliminated, mAbs reacting with hCGß-specific epitopes bound to hCGß and hCGß-R68E with identical affinities. In a separate series of experiments, we observed that LH cross-reactive epitopes were silent after immunization with a plasmid encoding a membrane form of hCGß-R68E, as previously observed with the soluble mutant protein itself. In contrast, the plasmid encoding the soluble secreted form of hCGß-R68E evoked LH cross-reactive antibodies, albeit of relatively low titer, suggesting that the handling and processing of the proteins produced by the two constructs differed.

Item Type:Article
Research Areas:A. > School of Science and Technology > Natural Sciences
A. > School of Science and Technology > Natural Sciences > Biomarkers for Cancer group
ID Code:3911
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Deposited On:02 Feb 2010 09:05
Last Modified:06 Oct 2015 11:32

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