A molecular mechanism for the activation of the first component of complement by immune complexes

• Published in: Molecular immunology Vol. 23; no. 5; p. 557
• Main Authors: Schumaker, V N, Hanson, D C, Kilchherr, E, Phillips, M L, Poon, P H
• Format: Journal Article
• Language: English
• Published: England 01-05-1986
• Subjects: Antigen-Antibody Complex - immunology; Antigen-Antibody Complex - metabolism; Complement Activating Enzymes; Complement Activation; Complement C1 - metabolism; Complement C1 Inactivator Proteins - metabolism; Complement C1q; Complement C1r; Complement C1s; Models, Molecular; Structure-Activity Relationship
• ISSN: 0161-5890
• DOI: 10.1016/0161-5890(86)90119-7

The proposed activation mechanism is based upon several key concepts, including the "S"-structure for the folding of the C1r2C1s2 tetramer among the C1q arms [Poon, et al., J. molec. Biol. 168, 563-577 (1983)]; the locations of the catalytic domains on the tetramer and the resulting functional relevance of the "S"-structure [Colomb et al., Phil. Trans. R. Soc. B306, 282-292 (1984)]; the structure of C1-inhibitor [Odermatt et al., FEBS Lett. 131, 283-289 (1981)]; and the control of C1 activation by C1-inhibitor [Ziccardi, J. Immun. 128, 2505-2508 (1982)]. The proposed activation mechanism has four main features: steric exclusion of C1-inhibitor from C1 when it binds to an immune complex; signal generation through multivalent binding of the C1q heads to an irregularly-arranged cluster of antibody Fc regions, and signal transmission through the movement of the stiff C1q arms about their semi-flexible joints, causing distortion of the symmetrical cone of C1q arms; induction of rapid activation by a shift in equilibrium favoring the autocatalytic conformation of C1r2C1s2; and release of the activated C1s from the C1q arms, so that the ends of the tetramer are free for interaction with C4 and C2 and C1-inhibitor, and the C1q subcomponent becomes more flexible, allowing access of C1-inhibitor to C1r.