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Active Disassembly of the First Complement Component, C, by C Inactivator¹

From the Department of Molecular Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037

Abstract

In order to clarify its mechanism of disassembly, the first component of human complement, C1, was reconstituted from C1q, ¹²⁵I-C1r, and ¹³¹I-C1s. This radiolabeled C1 bound tightly to aggregated IgG covalently linked to Sepharose 4B. The subsequent addition of C inactivator (C-In) led to the rapid release of equimolar quantitites of ¹²⁵I-C1 and ¹³¹I-C1 from the agg IgG. SDS-PAGE analyses of such eluates showed that one C-In molecule was associated with each C1 polypeptide chain and another C-In molecule was bound to each C1 polypeptide chain. The released C1, C1, and C-In co-sedimented in sucrose density gradients with a rate of 9S and monospecific anti-C1 pelleted all three proteins. Therefore, C1, C1, and C-In, in a molar ratio of 1:1:2, respectively, are released from C as a complex.

An analogous 9S complex containing C1, C1, and C-In was generated in normal human serum after incubation with activators of the classical complement pathway. The C1C1(C-In) complexes generated in both serum and the purified system were stable in the presence of EDTA.

A diffusion coefficient of 2.3 x 10^-7 cm²/sec was determined for the C1C1(C-In) complex from its behavior on gel filtration. An m.w. of 330,000 was then calculated from its sedimentation and diffusion coefficients. This m.w. is consistent with the value of 382,000 for a molecule of composition C1C1(C-In)₂ obtained by summing the weights of the subunits. These results indicate that C1-In efficiently disassembles C, thereby releasing two C1C1(C-In)₂ complexes per C molecule.

Footnotes

¹ This is publication No. 1758 from the Research Institute of Scripps Clinic. This work was supported by United States Public Health Service Grants CA 14692, AI 07007, AI 14502, 1 S07 RR 05514 from the National Institutes of Health and Grant-in-Aid 77-941 from the American Heart Association.

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