An IgG primary sequence exposure theory for complement activation using synthetic peptides [29]

Robert J. Boackle, Brian J. Johnson, Gretchen B Caughman

Research output: Contribution to journalLetter

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)742-743
Number of pages2
JournalNature
Volume282
Issue number5740
DOIs
StatePublished - Dec 1 1979
Externally publishedYes

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Complement Activation
Immunoglobulin G
Peptides
Antigens
Rabbits
Immunoglobulin Fc Fragments
Antibodies
Ultracentrifugation
Disulfides
Immunoglobulins
Amino Acid Sequence
Hot Temperature
Electrons

ASJC Scopus subject areas

  • General

Cite this

An IgG primary sequence exposure theory for complement activation using synthetic peptides [29]. / Boackle, Robert J.; Johnson, Brian J.; Caughman, Gretchen B.

In: Nature, Vol. 282, No. 5740, 01.12.1979, p. 742-743.

Research output: Contribution to journalLetter

Boackle, Robert J. ; Johnson, Brian J. ; Caughman, Gretchen B. / An IgG primary sequence exposure theory for complement activation using synthetic peptides [29]. In: Nature. 1979 ; Vol. 282, No. 5740. pp. 742-743.
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