A molecular mechanism for the activation of the first component of complement by immune complexes.
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.
D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism; D003166:Complement Activating Enzymes; D003167:Complement Activation; D003172:Complement C1 / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D015922:Complement C1q; D015923:Complement C1r; D003173:Complement C1s; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000936:Antigen-Antibody Complex; D003172:Complement C1; D003174:Complement C1 Inactivator Proteins; D015922:Complement C1q; D003166:Complement Activating Enzymes; D015923:Complement C1r; D003173:Complement C1s