C4B_2
gene geneOn this page
Summary
C4B_2 (complement component 4B (Chido/Rodgers blood group), copy 2, HGNC:42398) is a protein-coding gene on chromosome 6p21.3 alternate reference locus, encoding Complement C4-B (P0C0L5). Precursor of non-enzymatic components of the classical, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.
This gene encodes the basic form of complement factor 4, part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. In addition, this gene exists as a long form and a short form due to the presence or absence of a 6.4 kb endogenous HERV-K retrovirus in intron 9. This GeneID and its associated RefSeq record represent a second copy of C4B found on ALT_REF_LOCI_7.
Source: NCBI Gene 100293534 — RefSeq curated summary.
At a glance
- GWAS associations: 16
- MANE Select transcript:
NM_001242823
Identifiers
Gene identifiers
| Field | Value |
|---|---|
| HGNC ID | HGNC:42398 |
| Approved symbol | C4B_2 |
| Name | complement component 4B (Chido/Rodgers blood group), copy 2 |
| Location | 6p21.3 alternate reference locus |
| Locus type | gene with protein product |
| Status | Approved |
| Ensembl gene | ENSG00000233312 |
| Entrez | 100293534 |
Gene structure
Transcript identifiers
Ensembl transcripts: 0
RefSeq mRNA: 1 — MANE Select: NM_001242823
NM_001242823
Canonical transcript exons
ENST00000435500 — 0 exons
Expression profiles
Top tissues by expression
0 total, by Bgee expression score (0-100, higher = more expressed):
Regulation
Is transcription factor: no
Cross-species orthologs
0 orthologs
Protein
Protein identifiers
Complement C4-B — P0C0L5 (reviewed: P0C0L5)
Alternative names: Basic complement C4, C3 and PZP-like alpha-2-macroglobulin domain-containing protein 3
All UniProt accessions (2): A0A0G2JL54, P0C0L5
UniProt curated annotations — full annotation on UniProt →
Function. Precursor of non-enzymatic components of the classical, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. Non-enzymatic component of C3 and C5 convertases. Generated following cleavage by complement proteases (C1S, MASP2 or GZMK, depending on the complement pathway), it covalently attaches to the surface of pathogens, where it acts as an opsonin that marks the surface of antigens for removal. It then recruits the serine protease complement C2b to form the C3 and C5 convertases, which cleave and activate C3 and C5, respectively, the next components of the complement pathways. Complement C4b-B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens, while C4b-A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens. Putative humoral mediator released following cleavage by complement proteases (C1S, MASP2 or GZMK, depending on the complement pathway). While it is strongly similar to anaphylatoxins, its role is unclear. Was reported to act as a mediator of local inflammatory process; however these effects were probably due to contamination with C3a and/C5a anaphylatoxins in biological assays.
Subunit / interactions. In absence of complement activation, circulates in blood as a disulfide-linked trimer of an alpha, beta and gamma chain. Complement C4b is composed of complement C4b-A, complement C4 beta and complement C4 gamma chains that are associated via disulfide bonds. Non-enzymatic component of the C3 convertase, also named C4bC2b, composed of the serine protease complement C2b (C2), as well as complement C4b. Non-enzymatic component of the C5 convertase, also named C4bC2bC3b, composed of the serine protease complement C2b (C2), complement C3b, as well as complement C4b. Interacts with CR1 (via Sushi 1 and Sushi 2 domains). (Microbial infection) Binds B.burgdorferi OspC, the interaction is inhibited by complement factor C2. This binding may inhibit the complement cascade and allow the bacteria to survive in the host bloodstream.
Subcellular location. Secreted. Synapse. Cell projection. Axon. Dendrite Secreted Secreted. Cell surface.
Tissue specificity. Complement component C4 is expressed at highest levels in the liver, at moderate levels in the adrenal cortex, adrenal medulla, thyroid gland, and the kidney, and at lowest levels in the heart, ovary, small intestine, thymus, pancreas and spleen. The extra-hepatic sites of expression may be important for the local protection and inflammatory response.
Post-translational modifications. Prior to secretion, the single-chain precursor is enzymatically cleaved by plasminogen (PLG) to yield non-identical chains alpha, beta and gamma. During activation of the complement systems, the alpha chain is cleaved into C4a and C4b by different proteases depending on the complement pathway: C4b stays linked to the beta and gamma chains, while C4a is released in the plasma. The alpha chain is cleaved by C1S to generate C4a and C4b following activation by the classical complement system. The alpha chain is cleaved to generate C4a and C4b by MASP2 following activation by the lectin complement system. The alpha chain is cleaved by GZMK to generate C4a and C4b following activation by the GZMK complement system. Further degradation of C4b by C1 into the inactive fragments C4c and C4d blocks the generation of C3 convertase. The proteolytic cleavages often are incomplete so that many structural forms can be found in plasma. Upon activation, the internal thioester bond reacts with carbohydrate antigens on the target surface to form amide or ester bonds, leading to covalent association with the surface of pathogens. Complement C4b interacts with complement C3b via a thioester linkage. N- and O-glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.
Disease relevance. Systemic lupus erythematosus (SLE) [MIM:152700] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE. Complement component 4B deficiency (C4BD) [MIM:614379] A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis. The disease is caused by variants affecting the gene represented in this entry.
Polymorphism. The complement component C4 is the most polymorphic protein of the complement system. It is the product of 2 closely linked and highly homologous genes, C4A and C4B. Once polymorphic variation is discounted, the 2 isotypes differ by only 4 amino acids at positions 1120-1125: PCPVLD for C4A and LSPVIH for C4B. The 2 isotypes bear several antigenic determinants defining Chido/Rodgers blood group system [MIM:614374]. Rodgers determinants are generally associated with C4A allotypes, and Chido with C4B. Variations at these loci involve not only nucleotide polymorphisms, but also gene number and gene size. The second copy of C4B gene present in some individuals has been called C4B_2 by the HUGO Gene Nomenclature Committee (HGNC). Some individuals may lack either C4A, or C4B gene. Partial deficiency of C4A or C4B is the most commonly inherited immune deficiency known in humans with a combined frequency over 31% in the normal Caucasian population. Common copy-number variants of C4A and C4B affecting expression of complement component C4 in the brain have been associated with schizophrenia risk.
RefSeq proteins (1): NP_001229752* (*=MANE)
Domains & families (InterPro)
| ID | Name | Type |
|---|---|---|
| IPR000020 | Anaphylatoxin/fibulin | Domain |
| IPR001134 | Netrin_domain | Domain |
| IPR001599 | Macroglobln_a2 | Domain |
| IPR001840 | Anaphylatoxn_comp_syst_dom | Domain |
| IPR002890 | MG2 | Domain |
| IPR008930 | Terpenoid_cyclase/PrenylTrfase | Homologous_superfamily |
| IPR008993 | TIMP-like_OB-fold | Homologous_superfamily |
| IPR009048 | A-macroglobulin_rcpt-bd | Domain |
| IPR011625 | A2M_N_BRD | Domain |
| IPR011626 | Alpha-macroglobulin_TED | Domain |
| IPR013783 | Ig-like_fold | Homologous_superfamily |
| IPR018081 | Anaphylatoxin_comp_syst | Homologous_superfamily |
| IPR018933 | Netrin_module_non-TIMP | Domain |
| IPR019742 | MacrogloblnA2_CS | Conserved_site |
| IPR036595 | A-macroglobulin_rcpt-bd_sf | Homologous_superfamily |
| IPR040839 | MG4 | Domain |
| IPR041555 | MG3 | Domain |
| IPR047565 | Alpha-macroglob_thiol-ester_cl | Conserved_site |
| IPR048847 | C4_MG1 | Domain |
| IPR050473 | A2M/Complement_sys | Family |
| IPR054587 | CO4A-B_CUB_C | Domain |
Pfam: PF00207, PF01759, PF01821, PF01835, PF07677, PF07678, PF07703, PF17789, PF17791, PF21145, PF22661
UniProt features (143 total): strand 68, disulfide bond 16, helix 13, sequence conflict 9, sequence variant 8, chain 6, mutagenesis site 5, modified residue 4, glycosylation site 4, domain 2, site 2, propeptide 2, turn 2, signal peptide 1, cross-link 1
Structure
Experimental structures (PDB)
4 structures.
| PDB | Method | Resolution (Å) |
|---|---|---|
| 9U60 | ELECTRON MICROSCOPY | 2.9 |
| 9U5Z | ELECTRON MICROSCOPY | 3.1 |
| 9U61 | ELECTRON MICROSCOPY | 3.1 |
| 6YSQ | X-RAY DIFFRACTION | 3.3 |
Predicted structure (AlphaFold)
| Model | pLDDT | Fraction very-high |
|---|---|---|
| AF-P0C0L5-F1 | 83.50 | 0.44 |
Antibody-complex structures (SAbDab): 1 — 6YSQ
Functional residue map
Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.
Catalytic / active sites (2): 756–757 (cleavage; by c1s, masp2 and gzmk); 1125 (responsible for effective binding to form amide bonds with immune aggregates or protein antigens)
Post-translational modifications (5): 918, 1417, 1420, 1422, 1010–1013
Disulfide bonds (16): 68–97, 567, 635–669, 702–728, 703–735, 716–736, 820, 876, 1394, 1471–1535, 1566, 1583–1588, 1590, 1595–1673, 1618–1742, 1718–1727
Glycosylation sites (4): 226, 862, 1328, 1391
Mutagenesis-validated functional residues (5):
| Position | Phenotype |
|---|---|
| 1120 | no effect on hemolytic activity, nor on c1-dependent binding to igg. |
| 1121 | 30-40% decrease in hemolytic activity and c1-dependent binding to igg. |
| 1124 | 50-60% decrease in hemolytic activity and c1-dependent binding to igg. |
| 1125 | 20% decrease in hemolytic activity, 2-fold increase in c1-dependent binding to igg. |
| 1125 | 2.5-3 fold-decrease in hemolytic activity, 3-fold increase in c1-dependent binding to igg. |
Function
Pathways and Gene Ontology
Reactome pathways
4 pathways
| ID | Pathway |
|---|---|
| R-HSA-166663 | Initial triggering of complement |
| R-HSA-174577 | Activation of C3 and C5 |
| R-HSA-977606 | Regulation of Complement cascade |
| R-HSA-9920588 | Dengue virus activates/modulates innate and adaptive immune responses |
MSigDB gene sets: 12 (showing top):
REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_COMPLEMENT_CASCADE, REACTOME_ACTIVATION_OF_C3_AND_C5, REACTOME_INFECTIOUS_DISEASE, BIOCARTA_LECTIN_PATHWAY, REACTOME_VIRAL_INFECTION_PATHWAYS, REACTOME_DENGUE_VIRUS_INFECTION, REACTOME_DENGUE_VIRUS_HOST_INTERACTIONS, REACTOME_DENGUE_VIRUS_ACTIVATES_MODULATES_INNATE_AND_ADAPTIVE_IMMUNE_RESPONSES, REACTOME_INITIAL_TRIGGERING_OF_COMPLEMENT, BIOCARTA_CLASSIC_PATHWAY, BIOCARTA_COMP_PATHWAY
GO Biological Process (9): inflammatory response (GO:0006954), complement activation (GO:0006956), complement activation, classical pathway (GO:0006958), opsonization (GO:0008228), detection of molecule of bacterial origin (GO:0032490), complement activation, GZMK pathway (GO:0160257), positive regulation of apoptotic cell clearance (GO:2000427), immune system process (GO:0002376), innate immune response (GO:0045087)
GO Molecular Function (4): complement binding (GO:0001848), endopeptidase inhibitor activity (GO:0004866), carbohydrate binding (GO:0030246), protein binding (GO:0005515)
GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), synapse (GO:0045202), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), symbiont cell surface (GO:0106139), cell projection (GO:0042995)
Reactome top-level categories
Rollup of top-2 pathways:
| Category | Pathways |
|---|---|
| Complement cascade | 3 |
| Dengue Virus-Host Interactions | 1 |
GO top-level categories
Rollup of top GO terms by namespace:
| Category | Terms |
|---|---|
| cellular anatomical structure | 4 |
| immune effector process | 2 |
| complement activation | 2 |
| binding | 2 |
| neuron projection | 2 |
| defense response | 1 |
| activation of immune response | 1 |
| humoral immune response | 1 |
| protein activation cascade | 1 |
| humoral immune response mediated by circulating immunoglobulin | 1 |
| phagocytosis, recognition | 1 |
| response to molecule of bacterial origin | 1 |
| detection of chemical stimulus | 1 |
| detection of external biotic stimulus | 1 |
| innate immune response | 1 |
| apoptotic cell clearance | 1 |
| positive regulation of phagocytosis | 1 |
| regulation of apoptotic cell clearance | 1 |
| biological_process | 1 |
| immune response | 1 |
| defense response to symbiont | 1 |
| protein binding | 1 |
| endopeptidase activity | 1 |
| peptidase inhibitor activity | 1 |
| endopeptidase regulator activity | 1 |
| membrane | 1 |
| cell periphery | 1 |
| dendritic tree | 1 |
| cell junction | 1 |
| extracellular vesicle | 1 |
| extracellular region | 1 |
| other organism part | 1 |
Protein interactions and networks
STRING
0 interactions, top by confidence (×1000):
IntAct
36 interactions, top by confidence:
| A | B | Type | Score |
|---|---|---|---|
| CFHR4 | CRP | psi-mi:“MI:0915”(physical association) | 0.800 |
| KIF22 | KPNA4 | psi-mi:“MI:0914”(association) | 0.730 |
| C4B | C4A | psi-mi:“MI:0915”(physical association) | 0.720 |
| MASP2 | C4A | psi-mi:“MI:0407”(direct interaction) | 0.680 |
| C4A | MASP2 | psi-mi:“MI:0570”(protein cleavage) | 0.680 |
| CFHR1 | CRP | psi-mi:“MI:0915”(physical association) | 0.540 |
| MASP1 | C4A | psi-mi:“MI:0915”(physical association) | 0.400 |
| C4A | psi-mi:“MI:0915”(physical association) | 0.400 | |
| MASP2 | C4A | psi-mi:“MI:0915”(physical association) | 0.400 |
| CD5L | psi-mi:“MI:0915”(physical association) | 0.400 | |
| LECT2 | psi-mi:“MI:0915”(physical association) | 0.400 | |
| C4B | BNLF2 | psi-mi:“MI:0915”(physical association) | 0.370 |
| Tor1aip1 | PEX10 | psi-mi:“MI:0914”(association) | 0.350 |
| Naa10 | MYO9A | psi-mi:“MI:0914”(association) | 0.350 |
| Zbtb7a | C4B | psi-mi:“MI:0914”(association) | 0.350 |
| Uso1 | GOLGA2 | psi-mi:“MI:0914”(association) | 0.350 |
| MAPT | SHTN1 | psi-mi:“MI:0914”(association) | 0.350 |
| GNG8 | POTEF | psi-mi:“MI:0914”(association) | 0.350 |
| PPP2R2B | A2ML1 | psi-mi:“MI:0914”(association) | 0.350 |
| CCR1 | UBA6 | psi-mi:“MI:0914”(association) | 0.350 |
| C18orf21 | A2ML1 | psi-mi:“MI:0914”(association) | 0.350 |
| AGPAT1 | A2ML1 | psi-mi:“MI:0914”(association) | 0.350 |
| PHF11 | A2ML1 | psi-mi:“MI:0914”(association) | 0.350 |
BioGRID (19): C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C2 (Reconstituted Complex), C2 (Reconstituted Complex), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Proximity Label-MS), C4B (Affinity Capture-MS), C4B_2 (Affinity Capture-MS), C3 (Cross-Linking-MS (XL-MS)), C4B (Cross-Linking-MS (XL-MS))
ESM2 similar proteins: A0AAQ4VMX2, A0M8R7, A1X150, I2C090, O02668, P01029, P01030, P01031, P06238, P06684, P08581, P08649, P08650, P0C0L4, P0C0L5, P14046, P16056, P19069, P19823, P28665, P28666, P79263, P97523, P98093, P98094, Q00685, Q03626, Q07DY1, Q07DZ1, Q07E48, Q09YN5, Q108U6, Q14624, Q2IBA6, Q2IBC0, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9
Diamond homologs: A0AAQ4VMX2, P01029, P01030, P08649, P0C0L4, P0C0L5, P19069, P23667, Q2UVX4, Q6IE37, A0RZC6, I2C090, J3S836, P01024, P01025, P01026, P01027, P12247, P12387, P98093, P98094, Q00685, Q01833, Q0ZZJ6, Q6ZMU1, Q91132, P12082, P01032, P01023, P06238, P14046, P20740, P20742, P28666, Q03626, Q3UU35, Q5R4N8, Q61838, Q63041, Q6GQT1
SIGNOR signaling
11 interactions.
| A | Effect | B | Mechanism |
|---|---|---|---|
| CSMD1 | “down-regulates quantity” | C4B | binding |
| C4B | “form complex” | “C3 convertase complex” | binding |
| MASP2 | “up-regulates activity” | C4B | cleavage |
| MASP1 | “up-regulates activity” | C4B | cleavage |
| “Complement C1 complex” | “up-regulates activity” | C4B | cleavage |
Disease & clinical
Clinical variants and AI predictions
ClinVar
0 variants total. Per-class counts are floors (≥ shown; pagination cap):
| Classification | Count (floor) |
|---|---|
| Pathogenic | 0 |
| Likely pathogenic | 0 |
| Uncertain significance | 0 |
| Likely benign | 0 |
| Benign | 0 |
Top pathogenic / likely-pathogenic (0)
SpliceAI
0 predictions. Top by Δscore:
AlphaMissense
0 scored. Top likely-pathogenic:
dbSNP variants (sampled 300 via entrez): RS1000726010 (6:31995990 C>T), RS1001158549 (6:31980963 G>A), RS1001324282 (6:31998009 C>A,T), RS1002089632 (6:31996854 T>C), RS1004522192 (6:31996675 A>C,G), RS1006636511 (6:31980195 A>C), RS1009388336 (6:31980931 T>A), RS1009407914 (6:31980525 G>C,T), RS1016397819 (6:31996738 C>T), RS1017526214 (6:31981026 C>A,T), RS1020568425 (6:31997356 G>A), RS1020820448 (6:31980952 T>C), RS1020851383 (6:31980551 A>G), RS1023015049 (6:31980238 G>A,C), RS1030024956 (6:31994183 G>A)
Disease associations
OMIM: gene `` | disease phenotypes:
GenCC curated gene-disease
Mondo (0):
Orphanet (0):
HPO phenotypes
0 total (0 of 0 shown, HPO-id order):
GWAS associations
16 associations (top):
| Study | Trait | p-value |
|---|---|---|
| GCST004521_114 | Autism spectrum disorder or schizophrenia | 3.000000e-17 |
| GCST004521_117 | Autism spectrum disorder or schizophrenia | 3.000000e-15 |
| GCST004521_118 | Autism spectrum disorder or schizophrenia | 3.000000e-15 |
| GCST004521_126 | Autism spectrum disorder or schizophrenia | 2.000000e-10 |
| GCST004521_154 | Autism spectrum disorder or schizophrenia | 3.000000e-08 |
| GCST004521_17 | Autism spectrum disorder or schizophrenia | 2.000000e-12 |
| GCST004521_170 | Autism spectrum disorder or schizophrenia | 4.000000e-14 |
| GCST004521_173 | Autism spectrum disorder or schizophrenia | 4.000000e-14 |
| GCST004521_209 | Autism spectrum disorder or schizophrenia | 5.000000e-16 |
| GCST004521_211 | Autism spectrum disorder or schizophrenia | 5.000000e-15 |
| GCST004521_213 | Autism spectrum disorder or schizophrenia | 5.000000e-13 |
| GCST004521_227 | Autism spectrum disorder or schizophrenia | 4.000000e-12 |
| GCST004521_296 | Autism spectrum disorder or schizophrenia | 6.000000e-18 |
| GCST004521_45 | Autism spectrum disorder or schizophrenia | 2.000000e-16 |
| GCST004521_81 | Autism spectrum disorder or schizophrenia | 1.000000e-14 |
| GCST008916_30 | Asthma | 1.000000e-09 |
Drugs & pharmacology
Drug and pharmacology data
Is drug target: no
PharmGKB: 1 entry (VIP=true, CPIC=false)
CTD chemical–gene interactions
3 total (human), top 3 by PubMed support.
| Chemical | Actions (top 5) | PubMed papers |
|---|---|---|
| Diethylhexyl Phthalate | affects cotreatment, affects expression | 1 |
| Colforsin | affects cotreatment, affects expression | 1 |
| Smoke | decreases expression | 1 |
Clinical trials (associated diseases)
0 trials via MONDO — disease-level, not drug-specific.
Related Atlas pages
No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.