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Human IgG is produced in a pro-form that requires clipping of C-terminal lysines for maximal complement activation

Human IgG is produced with C-terminal lysines that are cleaved off in circulation. The function of this modification was unknown and generally thought not to affect antibody function. We recently reported that efficient C1q binding and complement-dependent cytotoxicity (CDC) requires IgG hexamerizat...

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Detalles Bibliográficos
Autores principales: van den Bremer, Ewald TJ, Beurskens, Frank J, Voorhorst, Marleen, Engelberts, Patrick J, de Jong, Rob N, van der Boom, Burt G, Cook, Erika M, Lindorfer, Margaret A, Taylor, Ronald P, van Berkel, Patrick HC, Parren, Paul WHI
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622059/
https://www.ncbi.nlm.nih.gov/pubmed/26037225
http://dx.doi.org/10.1080/19420862.2015.1046665
Descripción
Sumario:Human IgG is produced with C-terminal lysines that are cleaved off in circulation. The function of this modification was unknown and generally thought not to affect antibody function. We recently reported that efficient C1q binding and complement-dependent cytotoxicity (CDC) requires IgG hexamerization at the cell surface. Here we demonstrate that C-terminal lysines may interfere with this process, leading to suboptimal C1q binding and CDC of cells opsonized with C-terminal lysine-containing IgG. After we removed these lysines with a carboxypeptidase, maximal complement activation was observed. Interestingly, IgG1 mutants containing either a negative C-terminal charge or multiple positive charges lost CDC almost completely; however, CDC was fully restored by mixing C-terminal mutants of opposite charge. Our data indicate a novel post-translational control mechanism of human IgG: human IgG molecules are produced in a pro-form in which charged C-termini interfere with IgG hexamer formation, C1q binding and CDC. To allow maximal complement activation, C-terminal lysine processing is required to release the antibody's full cytotoxic potential.