Duplication and divergence of the amino-terminal coding region of the complement receptor 1 (CR1) gene. An example of concerted (horizontal) evolution within a gene.
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Human C3b/C4b receptor or complement receptor type one (CR1) is one of a family of receptor and regulatory glycoproteins that are encoded at a single genetic region (1q32) and are composed largely of a tandemly repeated motif (short consensus repeat or SCR) of approximately 60 amino acids. In addition, CR1 features an internal homology of seven SCRs in length, known as a long homologous repeat, that is reiterated four times, in the major polymorphic size variant, from SCR-1 to SCR-28, and may be reiterated three, five, and six times in other polymorphic forms. In the course of studying CR1, we detected sequences closely related to CR1 on several overlapping genomic clones. We have characterized a 40-kilobase CR1-like genomic region containing 10 potential exons that are 95% homologous to the amino-terminal coding portion of CR1. This region appears to be a partial duplication of CR1 and may encode a related gene. A comparison of CR1 and CR1-like sequences suggests that unequal crossing-over and concerted evolution have occurred within the most precisely reiterated subregion of CR1. Similar mechanisms have been important in the evolution of tandemly repeated genes and could provide the means for generation of the CR1 polymorphic size variants. (+info)
Oversulfated chondroitin sulfate inhibits the complement classical pathway by potentiating C1 inhibitor.
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Specific, sensitive, precise, and rapid functional chromogenic assay of activated first complement component (C1) in plasma.
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We present a new functional assay for the first complement component (C1) in plasma, based on its activation by inhibition of the C1-esterase inhibitor (C1-inh) when monospecific antiserum to C1-inh is added to the plasma. After maximal activation, we can determine the concentration of activated C1 by using an amidolytic rate assay with a chromogenic substrate. We have optimized the assay conditions with respect to incubation time, concentration of antiserum to C1-inh, ionic strength, and pH. Our method determines specifically the concentration in plasma of free activated C1, not complexes of activated C1 with C1-inh, and is not influenced by the concentration of C1-inh in the test sample. Concentrations of C1 correlated significantly with activities determined by a hemolytic assay (r = 0.55, t = 4.09, P less than 0.001). The estimated interassay CV was 5% and the intra-assay CV was 1%. The sensitivity, imprecision, and practical test performance of our assay are superior to those of conventionally used hemolytic assays. (+info)
Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation.
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Interaction of C1q subcomponent with immunoglobulin M.
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The affinity of human C1q subcomponent for IgM of normal human serum and Waldenstrom macroglobulins of patients Sew and Zuk were investigated by the polyethylene glycol 6,000 immune complexes precipitation test. This test was calibrated with heat-aggregated gamma-globulin (HAGG); maximum fixation of C1q ranged from 60 to 80% (measured as percentage of radioactivity of the immune complexes precipitate) and was observed when the C1q:HAGG concentration ratio was about 1:250. At the ratio of 1:20 the radioactivity of the precipitate was about 43% of the total. The capacity of polyclonal IgM and Waldenstrom macroglobulins for C1q fixation is low and variable. The percentage of C1q fixed at the C1q:IgM ratio of 1:20 for polyclonal IgM and Zuk macroglobulin was about 9%, whereas for Sew it was only about 1%. (+info)