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 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 (125)I-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. (125)I-C5 binds reversibly to C6 in an ionic strength-dependent fashion, but (125)I-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.
DiScipio
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La Jolla Institute for Experimental Medicine, La Jolla, California 92037, USA.
Linton
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Rushmere
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D000818:Animals; D016466:CHO Cells; D003183:Complement C6 / Q000737:chemistry / Q000502:physiology*; D003186:Complement C9 / Q000737:chemistry / Q000502:physiology; D017244:Complement Factor I / Q000737:chemistry / Q000502:physiology*; D003170:Complement Pathway, Alternative; D003171:Complement Pathway, Classical; D006224:Cricetinae; D006801:Humans; D011817:Rabbits; D012756:Sheep; D013329:Structure-Activity Relationship
D003183:Complement C6; D003186:Complement C9; D017244:Complement Factor I