TY - JOUR
T1 - An IgG primary sequence exposure theory for complement activation using synthetic peptides [29]
AU - Boackle, Robert J.
AU - Johnson, Brian J.
AU - Caughman, Gretchen B.
PY - 1979
Y1 - 1979
N2 - To establish the mechanism by which IgG, aggregating with antigen 1, triggers the first complement component2 (the C1q·C1r·C1s complex), it is important to distinguish the potential sites on the Fc region which may be involved in the interaction. Several studies have implicated the CH2 region of IgG3-5. C1 binds weakly to monomeric IgG but strongly to aggregated IgG6,7, and an analytical ultracentrifugation study of the binding of different IgG subclasses to the C1q subunit suggested that each C1q molecule may have from 12 to 18 receptor sites for immunoglobulin8. Although there are conflicting reports of conformational changes in antibody molecules induced by antigens 9-11, electron microscopic studies of rabbit IgG antibody 12 have shown that reduction of a single disulphide bond between the heavy chains in the hinge region allows this immunoglobulin, on contact with its antigen, to undergo strain-release conformational changes in the Fc region, suggesting a potential energy release and perhaps exposure of a cryptic site. Chemical modification of the tryptophanyl residues of both rabbit and human IgG or their Fc fragments has been shown to reduce then-C1-fixing potentials 13,14. These findings, together with examination of crystallographic structural data15 and amino acid sequence analyses16,17 of the CH2 region of human IgG1, support the possibility that a tryptophanyl residue in position 277 on human IgG (near the hinge region) could be in or near a site involved in the reaction with C1q. To explore this possibility, we have synthesised a series of small peptides resembling the portion of the CH2 region around the tryptophanyl residue at 277 (Table 1). A series of C1 consumption, C2 destruction, and C3 conversion tests was used to determine the most effective sequence for complement activation and to gain information about the functional nature of the interactions between the peptides and the human complement system. On the basis of these experiments we suggest that the primary structure of a small peptide segment is necessary for effective C1 binding and activation and that conformational changes caused by the reaction of IgG molecules with antigens, by heat aggregation, or by interfacial forces18 may expose this cryptic biologically active sequence.
AB - To establish the mechanism by which IgG, aggregating with antigen 1, triggers the first complement component2 (the C1q·C1r·C1s complex), it is important to distinguish the potential sites on the Fc region which may be involved in the interaction. Several studies have implicated the CH2 region of IgG3-5. C1 binds weakly to monomeric IgG but strongly to aggregated IgG6,7, and an analytical ultracentrifugation study of the binding of different IgG subclasses to the C1q subunit suggested that each C1q molecule may have from 12 to 18 receptor sites for immunoglobulin8. Although there are conflicting reports of conformational changes in antibody molecules induced by antigens 9-11, electron microscopic studies of rabbit IgG antibody 12 have shown that reduction of a single disulphide bond between the heavy chains in the hinge region allows this immunoglobulin, on contact with its antigen, to undergo strain-release conformational changes in the Fc region, suggesting a potential energy release and perhaps exposure of a cryptic site. Chemical modification of the tryptophanyl residues of both rabbit and human IgG or their Fc fragments has been shown to reduce then-C1-fixing potentials 13,14. These findings, together with examination of crystallographic structural data15 and amino acid sequence analyses16,17 of the CH2 region of human IgG1, support the possibility that a tryptophanyl residue in position 277 on human IgG (near the hinge region) could be in or near a site involved in the reaction with C1q. To explore this possibility, we have synthesised a series of small peptides resembling the portion of the CH2 region around the tryptophanyl residue at 277 (Table 1). A series of C1 consumption, C2 destruction, and C3 conversion tests was used to determine the most effective sequence for complement activation and to gain information about the functional nature of the interactions between the peptides and the human complement system. On the basis of these experiments we suggest that the primary structure of a small peptide segment is necessary for effective C1 binding and activation and that conformational changes caused by the reaction of IgG molecules with antigens, by heat aggregation, or by interfacial forces18 may expose this cryptic biologically active sequence.
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U2 - 10.1038/282742a0
DO - 10.1038/282742a0
M3 - Letter
C2 - 117384
AN - SCOPUS:0018686805
SN - 0028-0836
VL - 282
SP - 742
EP - 743
JO - Nature
JF - Nature
IS - 5740
ER -