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PubMed · 6180321

A molecular basis for the two locus model of human complement component C4.

M H Roos·E Mollenhauer·P Démant·C Rittner
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Abstract

The major histocompatibility complex(MHC)-linked fourth component of complement (C4) shows a high degree of polymorphism in several animal species. In man C4 polymorphism was detected by distinct charge differences of the variants. O'Neill et al. showed that this C4 polymorphism was controlled by two closely linked genetic loci, F (C4A) and S (C4B) and these results were extended by Awdeh et al. with an improved typing method. Biochemical analysis of human C4 has revealed that it consists of three polypeptide chains, alpha, beta and gamma. In all reports so far on the molecular analysis of human C4, no molecular weight differences between the A and B locus-encoded molecules have been noticed. Here we demonstrate that the C4A and C4B locus-encoded alpha-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C4A and C4B variants tested. Even rare variants that are difficult to allocate to the A or B locus on the basis of charge differences could be identified as C4A or C4B variants in this way, thereby providing new insights into the relationships between the C4A and C4B loci.

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Complement C4Electrophoresis, Polyacrylamide GelEpitopesGenetic VariationHumansMajor Histocompatibility ComplexMolecular WeightNeuraminidasePhenotypePolymorphism, GeneticSialic AcidsJournal ArticleResearch Support, Non-U.S. Gov't

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M H Roos, E Mollenhauer, P Démant, C Rittner. 1982-08-26. A molecular basis for the two locus model of human complement component C4.. https://doi.org/10.1038/298854a0

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Complex formation between the human complement proteins C4b and C2 was investigated by surface plasmon resonance. C4b was immobilised and C2 was used in the fluid phase to measure interaction at different ionic strengths (30-830 mM NaCl) and in the absence and presence of MgCl2. Maximum binding was observed at 30 mM NaCl, and was negligible above 300 mM NaCl. Binding was not greatly influenced by variation in Mg(2+) in the range of 2.5-15 mM. C4bC2 affinity (Kd) was determined by steady-state analysis to be 7.2x10(-8) M in physiological conditions (10 mM Hepes, 2.5 mM MgCl2, 0.75 mM CaCl2 and 140 mM NaCl, pH 7.4). For C4(H2O)C2 complex formation, a Kd of 4.0x10(-8) M was calculated. As far as detected by the applied method, complex formation does not involve conformational changes of one of the binding partners. Consistent with previous reports, C4bC2 binding takes place as a multiple-site binding event in the presence of Mg2+. C4bC2 complex formation in 10 mM Hepes, 2.5 mM EDTA and 140 mM NaCl (pH 7.4) was also observed and the interaction showed characteristics of a single-site binding event. Kd was 1.5x10(-8) M. Complement factor B (FB) was also tested for its binding to immobilised C4b. Weak interaction was observed at FB concentrations in the physiological range (500-1000 nM). Kd was 1.2x10(-6) M, indicating possible cross-reactivity between classical and alternative pathways of the activation of the complement system.

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