Complement C4-B (C4B_2)

The protein contains 1744 amino acids for an estimated molecular weight of 192751 Da.

 

Non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.', 'Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. (updated: April 1, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  3. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology.


Interpro domains
Total structural coverage: 93%
Model score: 27

(right-click above to access to more options from the contextual menu)

VariantDescription
allotype C4B-long
allotype C4B1-hi
allotype C4B-long and allotype C4B2
allotype C4B2 and allotype C4B5-Rg1
allotype C4B1a
allotype C4B5-Rg1
allotype C4B5-Rg1
allotype C4B1-SC01

The reference OMIM entry for this protein is 120820

Complement component 4b; c4b
Complement component 4f; c4f
Basic c4
C4, chido form

CLONING

By the process of antigen-antibody crossed electrophoresis, Rosenfeld et al. (1969) demonstrated heterogeneity in the fourth component of complement, C4. Using immunofixation electrophoresis and family studies, O'Neill et al. (1978) demonstrated that 2 different genetic loci control the electrophoretic patterns of C4. Studies by Awdeh and Alper (1980) provided direct evidence that 2 distinct but closely linked genes, C4A and C4B, encode C4. Both C3 (120700) and C4 are synthesized as single polypeptide chains (Brade et al., 1977; Hall and Colten, 1977). In serum, however, C3 consists of 2 polypeptide chains and C4 consists of 3 (Porter and Reid, 1978). Roos et al. (1982) showed that the alpha chains of C4A and C4B differ in molecular weight, being 96,000 and 94,000, respectively. Each C4 molecule consists of beta-alpha-gamma subunits, in that sequence, in the pro-C4. The secreted form of C4 is larger in molecular weight than the major plasma form by about 5,000 (Chan et al., 1983). Presumably, the extra piece is removed extracellularly by proteolytic cleavage. Yu et al. (1986) demonstrated that C4A and C4B differ by only 4 amino acids at position 1101 to 1106. Over this region C4A has the sequence PCPVLD, while C4B has the sequence LSPVIH. In a review of the molecular genetics of C4, Carroll and Alper (1987) stated that C4A and C4B differ by 14 nucleotides. Allotypic and serologic differences appear to result from single amino acid substitutions.

GENE STRUCTURE

Palsdottir et al. (1987) showed that the 2 human C4 genes differ in length because of the presence or absence of a 6.5-kb intron near the 5-prime end of the gene. The large intron was present in all C4A genes but only in some C4B genes. The C4A gene is usually approximately 22 kb long, whereas the C4B gene is polymorphic in size, either 22 or 16 kb. This size variation is due to the presence of a 7-kb intron located approximately 2.5 kb from the 5-prime end of the C4 genes (Prentice et al., 1986; Yu, 1991). A 6.4-kb insertion present in intron 9 in 60% of human C4 genes contains the complete human endogenous retrovirus-K(C4), or HERV-K(C4), in the reverse orientation to the C4 coding sequence. By expressing open reading frames from the HERV sequence in mouse cells transfected with either C4A or C4B, Schneider et al. (2001) demonstrated that the HERV-K(C4) antisense transcripts are present, that expression of the HERV-like constructs is significantly downregulated in cells expressing C4, and that gamma-interferon (147520)-induced upregulation of C4 enhances the downregulation of HERV in a dose-dependent manner.

MAPPING

The C4 locus in the guinea pig is linked to the major histocompatibility complex (Shevach et al., 1976) and to Bf (Kronke et al., 1977). The locus in man is in the major histocompatibility region on chromosome 6 (Teisberg et al., 1976; Ochs et al., 1977). The Ss protein of the mouse, determined by a gene that is part of the MHC complex, is homologous to C4 in man (Lachmann et al., 1975; Meo et al., 1975). Thus, linkage homology is maintained in 3 species. Pollack et al. (1980) used the linkage principle (and the tight linkage to HLA) for prenatal diagnosis of C4 deficiency. On the basis of 4 overlapping cosmid clones, Carroll et al. (1984) aligned 4 human complement genes known to map between HLA-D and HLA-B. The C2 and BF genes, which are less than 2 kb apart, are about 30 kb from the 2 C4 genes, which are separated from each ... More on the omim web site

The reference OMIM entry for this protein is 614374

Blood group, chido/rodgers system
Chido/rodgers blood group system

A number sign (#) is used with this entry because the Chido/Rodgers blood group system is based on variation in 2 closely linked genes, C4A (120810) and C4B (120820).

DESCRIPTION

The blood groups Chido (Ch) and Rodgers (Rg) are epitopes on the C4 protein, and polymorphisms associated with these epitopes may lead to the formation of antibodies to the Ch or Rg antigens in transfused patients. Identification of anti-Ch or anti-Rg is based on antibody neutralization with plasma from Ch-positive or Rg-positive individuals and lack of reactivity with qualified Ch-negative or Rg-negative red blood cells. The C4 protein occurs in 2 forms, C4A and C4B, which are encoded by 2 closely linked genes. C4A and C4B are expressed as single-chain precursors of 1,744 amino acids that are nearly identical, with amino acids differences at residues 1101 to 1106 distinguishing C4A from C4B. C4A and C4B are also distinguished by their expression of either the Ch antigen or the Rg antigen at residues 1188 to 1191, where the Ch1 epitope has ADLR and the Rg1 epitope has VDLL. C4A proteins usually carry the Rg antigens, and C4B proteins usually carry the Ch antigens, although in some haplotypes these associations are switched. Nine antigens have been described for the Ch/Rg system: 6 of high prevalence for Ch, 2 of high prevalence for Rg, and 1 of low prevalence, WH. Eight phenotypes of the Ch/Rg system have been established, with 88.2% of individuals having the Ch(1,2,3) Chido phenotype and 95.0% of individuals having the Rg(1,2) Rodgers phenotype (review by Mougey (2010)).

MOLECULAR GENETICS

Awdeh and Alper (1980) introduced a typing system that allowed them to detect 6 common structural alleles at the Rodgers (C4A) locus or 2 or 3 at the Chido (C4B) locus in whites.

HISTORY

The Chido blood group, which was discovered by Harris et al. (1967), is an antigenic characteristic of C4B. Chido has a low frequency of negatives (2%) and is tightly linked to HLA (Middleton and Crookston, 1972), closer to HLA-B (142830) than to HLA-A (14280). The Chido antigen resembles the HLA antigens in molecular structure. Like Chido, Rodgers has a low frequency of negatives (about 3%) and is closely linked to HLA (Giles et al., 1976). ... More on the omim web site

The reference OMIM entry for this protein is 152700

Systemic lupus erythematosus; sle excess lymphocyte low molecular weight dna, included
Excess lmw-dna, included

A number sign (#) is used with this entry because of evidence that multiple genes are involved in the causation of systemic lupus erythematosus.

DESCRIPTION

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008). - Genetic Heterogeneity of Systemic Lupus Erythematosus An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3. See

MAPPING

and

MOLECULAR GENETICS

sections for a discussion of genetic heterogeneity of susceptibility to SLE.

CLINICAL FEATURES

Lappat and Cawein (1968) suggested that drug-induced, specifically procainamide-induced, systemic lupus erythematosus is an expression of a pharmacogenetic polymorphism. Among close relatives of a procainamide SLE proband, they found antinuclear antibody in the serum in 3, and in all 5, 'significant' history or laboratory findings suggesting an immunologic disorder. Three had a coagulation abnormality. The finding of complement deficiency (see 120900) in cases of lupus as well as association with particular HLA types points to genetic factors responsible for familial aggregation of this disease. On the other hand, the evidence for viral etiology suggests nongenetic explanations. Lupus-like illness occurs (Schaller, 1972) in carriers of chronic granulomatous disease (306400). Lessard et al. (1997) demonstrated that CYP2D6 (124030) is the major isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus syndrome observed with procainamide. Lessard et al. (1999) stated that further studies were needed to demonstrate whether genetically-determined or pharmacologically-modulated low CYP2D6 activity could prevent drug-induced lupus during procainamide therapy. Reed et al. (1972) described inflammatory vasculitis with persistent nodules in members of 2 generations. Three females in the preceding generation had rheumatoid arthritis. They noted aggravation on exposure to sunlight and suppression of lesions with chloroquine therapy. They considered this to be related to lupus erythematosus profunda (Tuffanelli, 1971), which has a familial occurrence and is probably related to SLE. Brustein et al. (1977) described a woman with discoid lupus who had one child in whom lesions of discoid lupus began at age 2 months and a second child who developed a rash probably of lupus erythematosus at age 1 week. Sibley et al. (1993) described a family in which a brother and sister and a niece of theirs had SLE complicated by ischemic vasculopathy. Photographs of the hands and feet of 1 patient showing gangrene of several fingers and all toes were presented. Extensive osteonecrosis occurred in the niece. Elcioglu and Hall (1998) reported 2 sibs with chondrodysplasia punctata born to a mother with systemic lupus erythematosus. One child was stillborn at 36 weeks' gestation and the other miscarried ... More on the omim web site

The reference OMIM entry for this protein is 614379

Complement component 4b deficiency; c4bd
C4b deficiency

A number sign (#) is used with this entry because C4B deficiency is caused by mutation in the C4B gene (120820).

CLINICAL FEATURES

Partial deficiency of C4 was found in 3 persons during a screening of 42,000 healthy Japanese (Torisu et al., 1970). Of 26 patients with autoimmune chronic active hepatitis beginning in childhood, Vergani et al. (1985) found low C4 in 18 (69%) and low C3 serum levels in 5 (19%). Associated characteristics indicated a defect in synthesis of C4 and a genetic basis thereof was indicated by the fact that C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls. Homozygous deficiency of C4A (614380) is associated with systemic lupus erythematosus (152700) and with type I diabetes mellitus; homozygous deficiency of C4B is associated with susceptibility to bacterial meningitis (Winkelstein, 1987). In 3 African-American patients with systemic lupus erythematosus (SLE; 152700), Wilson and Perez (1988) found complete deficiency of plasma C4B. Lhotta et al. (1990) stated that only 17 cases of complete deficiency of C4 had been described. They described a patient with complete deficiency and renal disease, first presenting as severe Henoch-Schonlein purpura with renal involvement at the age of 17. Six years later, he developed hypertension and nephrotic syndrome, requiring hemodialysis followed by cadaveric kidney graft. After 2 years of uncomplicated course, the patient suffered a recurrence of his primary disease in the grafted kidney.

MOLECULAR GENETICS

Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient proband and provided evidence that the deficiency results from homozygosity for a rare, double-null haplotype. The family contained persons with 1, 2, 3, or 4 expressed C4 genes, and the mean serum C4 levels roughly reflected the number of structural genes present. To evaluate the molecular basis of the C4-null phenotypes, Partanen et al. (1988) used Southern blotting techniques to analyze genomic DNA from 23 patients with systemic lupus erythematosus (SLE; 152700) and from healthy controls. They confirmed the earlier findings of high frequencies of C4-null phenotypes and of HLA-B8,DR3 antigens. In addition, they found that among the patients most of both the C4A (120810)- and C4B-null phenotypes resulted from gene deletions. Among the controls, only the C4A-null phenotypes were predominantly the result of gene deletions. In all SLE cases, the C4 gene deletions extended also to a closely linked pseudogene, CYP21A (613815). Altogether, 52% of the patients and 26% of the controls carried a C4/CYP21A deletion. Partanen et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci fell within the range of 30 to 38 kb, as determined by pulsed-field gel electrophoresis. Because the deletion sizes in most other gene clusters were more heterogeneous, the results suggested to Partanen et al. (1989) the involvement of a specific mechanism in the generation of C4/CYP21 deletions. In a 9-year-old girl with SLE and complete C4 deficiency, Welch et al. (1990) found uniparental isodisomy 6. The girl had 2 identical chromosome 6 haplotypes from the father and none from the mother. Fasano et al. (1992) studied a 7-year-old patient with recurrent sinopulmonary infections in whom the rare C4A*Q0,B*Q0 double-null haplotype was shown to be due to a recombination event within the C ... More on the omim web site

Subscribe to this protein entry history

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 120820 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 152700 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 614379 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 120820 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 152700 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 614374 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 120820 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 614374 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 120820 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 614374 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 120820 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 614374 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 614379 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 614374 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 614379 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 120820 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 152700 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 614374 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 614379 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 152700 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 120820 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 120820 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 152700 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 614374 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 120820 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 614374 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 120820 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 614374 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 614379 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 120820 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 614374 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 120820 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 152700 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 614374 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 614379 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 614379 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 120820 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 152700 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 614374 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 614379 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 120820 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 152700 was added.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

June 20, 2017: Protein entry updated
Automatic update: comparative model was added.

March 25, 2017: Additional information
No protein expression data in P. Mayeux work for C4B_2

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 120820 was added.