Function of the Factor I Modules (FIMS) of Human Complement Component C6

In order to elucidate the function of complement component C6, truncated C6 molecules were expressed recombinantly. These were either deleted of the factor I modules (FIMs) (C6des-748–913) or both complement control protein (CCP) modules and FIMs (C6des-611–913). C6des-748–913 exhibited approximatel...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-11, Vol.274 (45), p.31811-31818
Main Authors: DiScipio, Richard G., Linton, Stuart M., Rushmere, Neil K.
Format: Article
Language:English
Subjects:
Animals
CHO Cells
Complement C6 - chemistry
Complement C6 - physiology
Complement C9 - chemistry
Complement C9 - physiology
complement component C6
complement control protein
complement factor I
Complement Factor I - chemistry
Complement Factor I - physiology
Complement Pathway, Alternative
Complement Pathway, Classical
Cricetinae
Humans
Rabbits
Sheep
Structure-Activity Relationship
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Summary:In order to elucidate the function of complement component C6, truncated C6 molecules were expressed recombinantly. These were either deleted of the factor I modules (FIMs) (C6des-748–913) or both complement control protein (CCP) modules and FIMs (C6des-611–913). C6des-748–913 exhibited approximately 60–70% of the hemolytic activity of full-length C6 when assayed for Alternative Pathway activity, but when measured for the Classical Pathway, C6des-748–914 was only 4–6% as effective as C6. The activity difference between C6 and C6des-748–913 for the two complement pathways can be explained by a greater stability of newly formed metastable C5b* when produced by the Alternative Pathway compared with that made by the Classical Pathway. The half-lives of metastable C5b* and the decay of 125I-C5b measured from cells used to activate the Alternative Pathway were found to be about 5–12-fold longer than those same parameters derived from cells that had activated the Classical Pathway. 125I-C5 binds reversibly to C6 in an ionic strength-dependent fashion, but 125I-C5 binds only weakly to C6des-FIMs and not at all to C6des-CCP/FIMs. Therefore, although the FIMs are not required absolutely for C6 activity, these modules promote interaction of C6 with C5 enabling a more efficient bimolecular coupling ultimately leading to the formation of the C5b-6 complex.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.45.31811