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PubMed1985

Polymorphism of human complement component C4.

An assessment has been made of the polymorphism of human complement component C4 by comparing derived amino acid sequences of cDNA and genomic DNA with limited amino acid sequences. In all, one complete and six partial sequences have been obtained from material from three individuals and include two C4A and two C4B alleles. Differences were found between the 4 alleles from 2 loci in only 15 of the 1722 amino acid residues, and 12 lie within one section of 230 residues, which in 1 allele also contains a 3-residue deletion. In three variable positions, an allelic difference in one C4 type was common to the other types. Three nucleotide differences were found in four introns. In spite of marked differences in their chemical reactivity, the many allelic forms appear to differ in less than 1% of their amino acid residue positions. This unusual pattern of polymorphism may be due to recent duplication of the C4 gene, or may have arisen by selection as a result of the biological role of C4, which interacts in the complement sequence with nine other proteins necessitating conservation of much of the surface structure.

Amino Acid Sequence↗
PubMed1989

Murine complement component C4 and sex-limited protein: identification of amino acid residues essential for C4 function.

Murine sex-limited protein (Slp) is an isotype of murine complement component C4 that shares 95% sequence identity with C4 as well as the intramolecular thioester necessary for C4 function but has no complement activity. Slp is nonfunctional at least in part because it is not cleaved by the activated form of complement protease C1s (C1s), which proteolytically activates C4 in the classical complement pathway. Slp is also distinct from C4 in that its expression in some mouse strains is under testosterone control. In the present studies, we used site-directed mutagenesis of C4 and expression of the mutant proteins in cultured cells to identify the amino acid substitutions in Slp that are responsible for resistance to C1s cleavage. We focused on sequence changes immediately downstream of the cleavage site in C4 because the arginine at that site is conserved in Slp, but the downstream sequences diverge substantially, with six differences in the first 7 residues followed by a 3-residue deletion in Slp. We found that a C4 mutant carrying only the 3-residue deletion is not cleaved by C1s and has essentially no hemolytic activity, whereas a mutant carrying only the six replacement changes is cleaved by C1s and has normal hemolytic activity. Both mutants have intact thioesters. A third mutant in which two acidic residues in the segment deleted in Slp were replaced by aliphatic residues is also cleaved by C1s, has an intact thioester group, and has normal hemolytic activity. These results indicate that the downstream mutations are responsible for the resistance of Slp to C1s cleavage and suggest that the length rather than the specific sequence of this segment is critical in determining susceptibility to the protease.

Amino Acid Sequence↗
PubMed2026

Complement component C4 and neuroimaging in psychiatry: A systematic review.

INTRODUCTION: Genomic, transcriptomic, and proteomic studies suggest that the complement system contributes to the pathophysiology of various psychiatric disorders partly through neurodevelopmental effects linked to C4A protein levels variations. We conducted a systematic review to characterize how brain micro- and macrostructure and connectivity vary with proxies of in vivo brain C4A protein levels in both psychiatric and general-population cohorts. METHODS: We used Medline, Web of Science, and Embase, and included all studies published before April 14, 2025. Inclusion criteria were: (1) inclusion of healthy controls and/or individuals with psychiatric disorders assessed according to recognized diagnostic manuals (DSM or ICD); (2) use of MRI-based neuroimaging; and (3) use of genomic, transcriptomic and/or proteomic approaches as proxies of in vivo brain C4A proteins levels. RESULTS: From 317 identified articles, 11 were included. Associations between C4A levels and brain structure were heterogeneous across regions. Only the mOFC, dlPFC, and entorhinal cortex were implicated in more than one study. Findings for the mOFC and dlPFC varied by the type of metrics and clinical status, whereas higher C4A levels were more consistently associated with smaller entorhinal cortex surface area and cortical thickness in pediatric, middle-aged, and older general-population cohorts. In addition, one study found higher genetically predicted C4A expression to be associated with higher TSPO levels. CONCLUSION: The limited number of available studies and their methodological heterogeneity make synthesis challenging. However, biological hypotheses such as excessive synaptic pruning or broader inflammatory effects on the brain may provide plausible explanatory frameworks for the reported associations.

Humans↗
PubMed1996

Production of the third and fourth component of complement (C3, C4) by smooth muscle cells.

Production of the third and fourth components of complement (C3, C4) by smooth muscle cells was investigated by using normal human aortic smooth muscle cells (AoSMC), human smooth muscle cell line (G402) and vascular smooth muscle cells obtained from human umbilical cord vein (UVSMC). AoSMC spontaneously produced both C3 and C4 at 15 ng/10(6) cells/72 hr and 22 ng/10(6) cells/72 hr, respectively, and both were enhanced by interferon-gamma (IFN-gamma). Although phorbol 12-myristate 13-acetate (PMA) and tumour necrosis factor-alpha (TNF-alpha) enhanced C3 production, C4 production was reduced by these agents. On the other hand, G402 produced C4 but not C3 in a dose-dependent manner when cultured with IFN-gamma. UVSMC produced only a small amount of C3 and C4 compared with AoSMC or G402. C3 and C4 produced by AoSMC were confirmed to be identical with their human serum counterparts as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and measurement of haemolytic activity. Northern blotting analysis showed that the expression of mRNA of C3 and C4 was enhanced by TNF-alpha and IFN-gamma, respectively, in AoSMC. Our findings suggest the importance of smooth muscle cells as a source of components of complement in vascular diseases including vasculitis.

Aorta↗
PubMed1986

Phenotyping of human complement component C4, a class-III HLA antigen.

The plasma complement protein C4 is encoded at two highly polymorphic loci, A and B, within the class-III region of the major histocompatibility complex. At least 34 different polymorphic variants of human C4 have been identified, including non-expressed or 'null' alleles. The main method of identification of C4 polymorphic allotypes is separation on the basis of charge by agarose-gel electrophoresis of plasma. On staining by immunofixation with anti-C4 antibodies, each C4 type gives three major bands, but, since individuals can have up to five allotypes, the overlapping banding pattern is difficult to interpret. We show that digestion of plasma samples with carboxypeptidase B, which removes C-terminal basic amino acids, before electrophoresis, produces a single, sharp, distinct band for each allotype and allows identification of the biochemical basis of the multiple banding pattern previously observed in C4 phenotype determination.

Carboxypeptidase B↗
PubMed1984

The structural basis of the multiple forms of human complement component C4.

cDNA clones of human complement components C4A and C4B alleles were prepared from mRNA obtained from the liver of a donor heterozygous at both loci. cDNA from one C4A allele was sequenced to give the derived complete amino acid sequence of 1722 amino acid residues of the C4 single chain precursor molecule and the estimated sequences of the three peptide chains of secreted C4. Comparison with partial sequences of a second C4A allele and a C4B allele has led to the tentative identification of some class differences in nucleotide sequences between C4A and C4B and of allelic differences between C4A alleles in this highly polymorphic system.

Amino Acid Sequence↗
PubMed1991

Complement C4-derived monocyte-directed chemotaxis-inhibitory factor. A molecular mechanism to cause polymorphonuclear leukocyte-predominant infiltration in rheumatoid arthritis synovial cavities.

To reveal the mechanism of the lesser infiltration of monocytes in synovial cavities with rheumatoid arthritis despite the presence of chronic inflammation, the synovial fluid from 15 rheumatoid arthritis patients was analyzed with respect to leukocyte chemotaxis. The synovial fluid possessed strong chemotactic activity to polymorphonuclear leukocytes but rather suppressed one to monocytes. The synovial fluid contained two different inhibitory activities in monocyte chemotaxis. One, which also suppressed polymorphonuclear leukocyte chemotaxis, was identified as alpha 1 protease inhibitor. The other, with molecular weight of 8 kd, possessed the specificity to monocytes and shared the antigenicity with complement C4 but not with C3 or C5. A similar inhibitor was generated in normal human plasma when the classical pathway of the complement system was initiated with aggregated human IgG, while it was not when alternative pathway was initiated with zymosan. The small size factor in the synovial fluid, apparently derived from C4, seemed to be a cyto-directed factor that might block an early part of signal transduction system of monocytes in the chemotaxis. After removal of the small-size inhibitor, the synovial fluid exhibited chemotactic ability to monocytes. Therefore the apparent C4-derived factor might play a key role in the polymorphonuclear leukocyte-predominant infiltration in the synovial fluid of rheumatoid arthritis.

Adult↗
PubMed1993

Effect of thiol compounds on human complement component C4.

Thiol compounds have been investigated as inhibitors of the covalent binding reaction of human complement protein C4 using Sepharose-C1s as a combined activating and binding surface. o- and p-substituted aminothiophenols are equally effective inhibitors, whereas the m-substituted compound is a less potent inhibitor. The anti-hypertensive drug captopril is also shown to inhibit the covalent binding reaction. A comparison of the effects of these compounds on the covalent binding reaction of isolated C4A and C4B has been made. Results suggest that a Pro-to-Leu substitution in C4B is likely to account for the differences in inhibitory potency of C4B compared with C4A observed with the aromatic inhibitors.

Aminophenols↗
PubMed1980

The binding of human complement component C4 to antibody-antigen aggregates.

The binding of human complement component C4 to antibody-antigen aggregates and the nature of the interaction have been investigated. When antibody-antigen aggregates with optimal C1 bound are incubated with C4, the C4 is rapidly cleaved to C4b, but only a small fraction (1-2%) is bound to the aggregates, the rest remaining in the fluid phase as inactive C4b. It has been found that C4b and th antibody form a very stable complex, due probably to the formation of a covalent bond. On reduction of the C4b-immunoglobulin G (IgG) complex, the beta and gamma chains, but not the alpha' chain, of C4b are released together with all the light chain, but only about half of the heavy chain of IgG. The reduced aggregates contain two main higher-molecular-weight complexes, one shown by the use of radioactive components to contain both IgG and C4b and probably therefore the alpha' chain of C4b and the heavy chain of IgG, and the other only C4b and probably an alpha' chain dimer. The aggregates with bound C1 and C4b show maximal C3 convertase activity, in the presence of excess C2, when the alpha'-H chain component is in relatively highest amounts. When C4 is incubated with C1s in the absence of aggregates, up to 15% of a C4b dimer is formed, which on reduction gives an alpha' chain complex, probably a dimer. The apparent covalent interaction between C4b and IgG and between C4b and other C4b molecules cannot be inhibited by iodoacetamide and hence cannot be catalysed by transglutaminase (factor XIII). The reaction is, however, inhibited by cadaverine and putrescine and 14C-labelled putrescine is incorporated into C4, again by a strong, probably covalent, bond. It is suggested that a reactive group, possibly an acyl group, is generated when C4 is activated by C1 and that this reactive group can react with IgG, with another C4 molecule, or with water.

Antigen-Antibody Complex↗
PubMed1984

A comparison of the properties of two classes, C4A and C4B, of the human complement component C4.

A remarkable difference has been observed between the reactivity of the two forms of human complement component C4. C4B binds twice as effectively as C4A to antibody-coated red cells, but the reverse occurs with protein-antigen complexes. C4B reacts much more effectively with hydroxyl groups than C4A and this is reversed for reaction with amino groups in spite of the very small difference in amino acid sequence between the two forms of C4. No other differences in stability, activation or inactivation were observed. These findings emphasise the biological advantage of the duplication of the C4 gene in its reaction with a wide range of antigenic structures. The correlation of the presence of different forms of C4 with susceptibility to autoimmune diseases may be explicable by these big differences in binding reactivity.

Amino Acid Sequence↗
PubMed1976

Persistence of immunoglobulin and complement components C4 and C3 bound to guinea pig tumor cells.

Guinea pig hepatoma cells (line-10) growing as ascites were studied for the presence of immunoglobulin, C4, and C3 (components of complement) on their surfaces. Immunoglobulin, C4, and C3 content increased with length of time spent in the peritoneal cavity. The persistence of these factors bound in vivo or in vitro was also determined. Complement-fixing (CF) activity of cellbound antibody disappeared from the surface more rapidly at 37 degrees C than at 4 degrees C; the continued presence of cellbound immunoglobulin in non-complement-fixing form could be demonostrated at either temperature. No CF activity was released into the medium. C4 and C3 were released into the medium and could be demonstrated in the medium by immunochemical methods.

Animals↗
PubMed1999

Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes.

The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele.

Adult↗
PubMed1987

The chemical structure of the C4d fragment of the human complement component C4.

The complete amino acid sequence of the C4d fragment (380 residues long) of the human complement component C4 is presented. Most of the sequence was determined by analysis of CNBr peptides and tryptic peptides obtained from S-carboxymethylated protein. The sequence of the amino terminal 88 residues [Campbell R. D., Gagnon J. and Porter R. R. (1981) Biochem. J. 199, 359-370] and a 106 residue polymorphic segment of C4d [Chakravarti D. N., Campbell R. D. and Gagon J. (1983) FEBS Lett. 154, 387-390] was extended. Some overlaps not provided by the protein sequence analysis were obtained from the amino acid sequence predicted by the nucleotide sequence [Belt K. T., Carroll M. C. and Porter R. R. (1984) Cell 36, 907-914]. The present protein sequence data provide information for the isolation of all the CNBr and succinylated tryptic peptides of C4d. In addition to the polymorphism previously described, two other sets of polymorphic amino acid residues at positions 153 (Ile/Ser) and 154 (Gln/Ala) have been identified. The major site of glycosylation has been shown to be an asparagine residue located in the sequence -Asn-Val-Thr- in the carboxy terminal end of C4d. A remarkable difference in the predicted secondary structure of C4d arising from one set of four polymorphic residues in a stretch of six residues and another single polymorphic residue suggests a structural basis for the origin of the different chemical reactivities of the C4 isotypes (C4A and C4B) and their serological difference in the expression of Rodgers or Chido blood group antigens. Possible non-covalent membrane attachment sites have been suggested from the hydropathy profile. Comparison of the C4d sequence with human C3, C5 and alpha 2-macroglobulin revealed extended stretches of sequence similarity (between 19 and 38% homology) with the corresponding regions of these proteins.

Amino Acid Sequence↗
PubMedDate not supplied

A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B.

Four human complement genes, which have previously been mapped between HLA-D and HLA-B on chromosome 6, have now been aligned on a 98-kilobase (kb) section of the chromosome on the basis of four overlapping cosmid clones of genomic DNA. The C2 and factor B genes, less than 2 kb apart, are about 30 kb from two C4 genes separated from each other by about 10 kb.

Chromosome Mapping↗
PubMed2004

[Human complement components C4 and Bf polymorphisms and their complotypes in Guangdong Chinese Han population].

OBJECTIVE: To investigate the genetic polymorphism of human complement components C(4) and Bf and their complotype frequencies in Chinese Han population in Guangdong Province of China. METHODS: The genetic polymorphisms and complotypes of Bf, C(4)A and C(4)B, which were 3 components of HLA-III, were analyzed in 144 chromosomes of subjects from healthy Han families in Guangdong Province. RESULTS: Thirteen variable complotypes were identified, led by the complotypes of S(32), S(31), S(42) and F(42) among which strong linkage disequilibria were observed. The most common phenotypes were BFS, C(4)A(3), C(4)A(4), C(4)B(2) and C(4)B(1). CONCLUSION: The genetic polymorphism of C(4) and Bf and their complotypes have their own genetic predisposition in Chinese Han population in Guangdong Province.

Asian People↗
PubMed1990

Conversion of the C4d.2 serologic allotype of murine complement component C4 to the C4d.1 allotype by site-specific mutagenesis.

C4d.1 and C4d.2 are serologically defined allotypes of murine complement component C4. Previous studies in Shreffler's laboratory have shown that the structural difference between the two allotypes lies within a single tryptic peptide of the C4 alpha-chain and that the sequences of this fragment from the two allotypes (determined from nucleic acid sequences of genomic clones) differ only by the substitution of arginine in C4d.2 for glutamine in C4d.1. Hence this single amino acid change apparently is responsible for the rather striking serological difference between the two allotypes. To test this conclusion, we have used site-specific mutagenesis to alter the sequence of a full-length C4 cDNA that was derived from a mouse strain expressing the C4d.2 allotype. We substituted a glutamine codon for the arginine codon at the specified site and expressed both mutant and parent recombinant C4 proteins by transient transfection of COS cells. We found that an alloantiserum specific for C4d.1 reacts with the mutant protein but not the parent whereas an alloantiserum specific for C4d.2 reacts with the parent protein, as expected, but not the mutant. These results confirm that a single amino acid difference specifies the C4d.1 and C4d.2 allotypes.

Alleles↗