C4BPB

Summary

C4BPB (complement component 4 binding protein beta, HGNC:1328) is a protein-coding gene on chromosome 1q32.1, encoding C4b-binding protein beta chain (P20851). Controls the classical pathway of complement activation.

This gene encodes a member of a superfamily of proteins composed predominantly of tandemly arrayed short consensus repeats of approximately 60 amino acids. A single, unique beta-chain encoded by this gene assembles with seven identical alpha-chains into the predominant isoform of C4b-binding protein, a multimeric protein that controls activation of the complement cascade through the classical pathway. C4b-binding protein has a regulatory role in the coagulation system also, mediated through the beta-chain binding of protein S, a vitamin K-dependent protein that serves as a cofactor of activated protein C. The genes encoding both alpha and beta chains are located adjacent to each other on human chromosome 1 in the regulator of complement activation gene cluster. Alternative splicing gives rise to multiple transcript variants.

Source: NCBI Gene 725 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 56 total
• MANE Select transcript: NM_001017365

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1328
Approved symbol	C4BPB
Name	complement component 4 binding protein beta
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000123843
Ensembl biotype	protein_coding
OMIM	120831
Entrez	725

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 30 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000243611, ENST00000367076, ENST00000367078, ENST00000391923, ENST00000452902, ENST00000469326, ENST00000470767, ENST00000492730, ENST00000873228, ENST00000873229, ENST00000873230, ENST00000873231, ENST00000873232, ENST00000873233, ENST00000873234, ENST00000873235, ENST00000873236, ENST00000873237, ENST00000873238, ENST00000873239, ENST00000873240, ENST00000873241, ENST00000873242, ENST00000873243, ENST00000873244, ENST00000873245, ENST00000873246, ENST00000873247, ENST00000873248, ENST00000873249, ENST00000873250, ENST00000873251, ENST00000949638

RefSeq mRNA: 5 — MANE Select: NM_001017365 NM_000716, NM_001017364, NM_001017365, NM_001017366, NM_001017367

CCDS: CCDS1476, CCDS31005

Canonical transcript exons

ENST00000367078 — 7 exons

Exon	Start	End
ENSE00000842592	207091644	207091820
ENSE00000842593	207096522	207096615
ENSE00001868098	207088860	207088946
ENSE00003559430	207090308	207090481
ENSE00003582401	207089482	207089589
ENSE00003622346	207098150	207098264
ENSE00003682186	207099789	207099993

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 99.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.0642 / max 887.7261, expressed in 130 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8183	1.3749	64
8193	1.0703	38
8185	0.5118	56
8190	0.1947	13
8197	0.1844	45
8194	0.1778	46
8196	0.1219	42
8182	0.0968	25
8198	0.0836	28
8191	0.0729	13

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.45	gold quality
liver	UBERON:0002107	98.31	gold quality
left ovary	UBERON:0002119	90.99	gold quality
right ovary	UBERON:0002118	89.04	gold quality
ovary	UBERON:0000992	85.23	gold quality
body of stomach	UBERON:0001161	80.23	gold quality
body of pancreas	UBERON:0001150	79.49	gold quality
triceps brachii	UBERON:0001509	79.43	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.71	gold quality
transverse colon	UBERON:0001157	76.00	gold quality
mucosa of stomach	UBERON:0001199	75.76	gold quality
stomach	UBERON:0000945	75.56	gold quality
pancreas	UBERON:0001264	74.59	gold quality
right lung	UBERON:0002167	74.54	gold quality
small intestine	UBERON:0002108	73.85	gold quality
gall bladder	UBERON:0002110	73.84	gold quality
duodenum	UBERON:0002114	73.53	gold quality
vermiform appendix	UBERON:0001154	72.92	gold quality
gluteal muscle	UBERON:0002000	72.75	gold quality
rectum	UBERON:0001052	71.91	gold quality
upper lobe of left lung	UBERON:0008952	71.16	gold quality
sperm	CL:0000019	71.07	silver quality
islet of Langerhans	UBERON:0000006	70.43	gold quality
caecum	UBERON:0001153	69.92	gold quality
mucosa of transverse colon	UBERON:0004991	69.91	gold quality
male germ cell	CL:0000015	69.42	silver quality
upper lobe of lung	UBERON:0008948	69.34	gold quality
fundus of stomach	UBERON:0001160	68.97	gold quality
intestine	UBERON:0000160	67.94	gold quality
placenta	UBERON:0001987	67.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA3, FOXM1, NFIA, NFIC, STAT3

Literature-anchored findings (GeneRIF, showing 20)

• Localized via protein S to the surface of apoptotic cells, C4BP is able to interact with complement protein C4b, thus retaining its physiological role in regulation of complement on the apoptotic cell surface. (PMID:12193728)
• C4BP is composed of seven alpha-chains and a unique beta-chain, each chain comprising repeating complement control protein (CCP) modules, the results suggest that the role of CCP2 in protein S binding is to orient and stabilize CCP1 (PMID:12492479)
• Localization of binding sites for a number of C4BP ligands in relation to well-established and novel functions of C4BP. Review (PMID:15179322)
• C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation. (PMID:15967823)
• analysis of structural basis for C4b-binding protein interaction with streptococcal M protein (PMID:16330538)
• review of multiple functional roles of the complex of protein S and cd4-binding protein beta chain, such as binding to apoptotoic cells, phagocytosis (PMID:17597997)
• C4BP levels are increased in patients suffering from primary Sjogren’s syndrome (PMID:19284503)
• C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4 (PMID:19494311)
• C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies. (PMID:20212171)
• Results demonstrate that successful secretion of complement regulatory protein C4b-binding protein beta-chains depends on intracellular complex formation with vitamin K-dependent protein S, but not on the alpha-chains. (PMID:20693287)
• crystallographic data on the structure of CD11c/CD18 and prediction of the secondary structure of the C4BP oligomerization domain, we show that epitopes bound by KIM185 in these proteins are unlikely to share any major structural similarity. (PMID:21856004)
• Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. (PMID:22514678)
• C4BP alpha7beta0 subunit [C4BP alpha7beta0 isoform lacking the beta-chain] induces a semimature, tolerogenic state on human monocyte-derived dendritic cells activated by a proinflammatory stimulus. (PMID:23390292)
• Binding of complement inhibitor C4b-binding protein to a highly virulent Streptococcus pyogenes M1 strain is mediated by protein H and enhances adhesion to and invasion of endothelial cells. (PMID:24064215)
• C4BPB/C4BPA may not confer susceptibility to schizophrenia among Han Chinese (PMID:25660618)
• C4BP is deposited in the diseased aortic valve, coincident with C3d expression. (PMID:26897815)
• Exposure to arterial blood pressure leads to a transient presence of C4bp in the saphenous vein wall. (PMID:28163174)
• SAA, PROZ, and C4BPB may serve as new potential biomarkers for TB (PMID:28278182)
• C4BP(beta-)-mediated immunomodulation attenuates inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients. (PMID:37806602)
• Higher-order structure and proteoforms of co-occurring C4b-binding protein assemblies in human serum. (PMID:38811852)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
rattus_norvegicus	C4bpb	ENSRNOG00000004125

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPA (ENSG00000123838), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

C4b-binding protein beta chain — P20851 (reviewed: P20851)

All UniProt accessions (2): P20851, Q5VVQ7

UniProt curated annotations — full annotation on UniProt →

Function. Controls the classical pathway of complement activation. It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then hydrolyzes the complement fragment C4b. It also accelerates the degradation of the C4bC2a complex (C3 convertase) by dissociating the complement fragment C2a. It also interacts with anticoagulant protein S and with serum amyloid P component. The beta chain binds protein S.

Subunit / interactions. Disulfide-linked complex of alpha and beta chains of 3 possible sorts: a 570 kDa complex of 7 alpha chains and 1 beta chain, a 530 kDa homoheptamer of alpha chains or a 500 kDa complex of 6 alpha chains and 1 beta chain. The central body of the alpha chain homomer supports tentacles, each with the binding site for C4b at the end.

Subcellular location. Secreted.

Isoforms (2)

UniProt ID	Names	Canonical?
P20851-1	1	yes
P20851-2	2

RefSeq proteins (5): NP_000707, NP_001017364, NP_001017365, NP_001017366, NP_001017367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily

Pfam: PF00084

UniProt features (21 total): disulfide bond 8, glycosylation site 5, domain 3, sequence variant 2, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20851-F1	82.06	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (8): 23–63, 49–76, 81–121, 107–134, 139–179, 165–191, 202, 216

Glycosylation sites (5): 64, 71, 98, 117, 154

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-977606	Regulation of Complement cascade
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses
R-HSA-166658	Complement cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 138 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GNF2_HPN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_WOUND_HEALING, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (8): complement activation, classical pathway (GO:0006958), blood coagulation (GO:0007596), response to symbiotic bacterium (GO:0009609), innate immune response (GO:0045087), positive regulation of protein catabolic process (GO:0045732), negative regulation of complement activation, classical pathway (GO:0045959), regulation of opsonization (GO:1903027), immune system process (GO:0002376)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Complement cascade	1
Dengue Virus-Host Interactions	1
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
humoral immune response mediated by circulating immunoglobulin	1
complement activation	1
hemostasis	1
wound healing	1
coagulation	1
response to symbiont	1
response to bacterium	1
immune response	1
defense response to symbiont	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
negative regulation of humoral immune response mediated by circulating immunoglobulin	1
complement activation, classical pathway	1
regulation of complement activation, classical pathway	1
negative regulation of complement activation	1
regulation of immune effector process	1
opsonization	1
regulation of cellular process	1
biological_process	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C4BPB	C4A	P01028	960
C4BPB	C4A	P01028	953
C4BPB	CFHR4	Q92496	755
C4BPB	C8A	P07357	744
C4BPB	CFHR2	P36980	716
C4BPB	CFHR3	Q02985	706
C4BPB	CFHR1	Q03591	690
C4BPB	C4BPA	P04003	658
C4BPB	CFI	P05156	620
C4BPB	C3	P01024	613
C4BPB	F5	P12259	605
C4BPB	C8G	P07360	583
C4BPB	CR1	P17927	582
C4BPB	C8B	P07358	567
C4BPB	CNDP2	Q96KP4	549

IntAct

8 interactions, top by confidence:

A	B	Type	Score
C4BPB	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
S	IGLL5	psi-mi:“MI:0914”(association)	0.350
C4BPB	DCTN6	psi-mi:“MI:0914”(association)	0.350
C4BPB	DCTN3	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (50): ZNF655 (Affinity Capture-MS), DCTN4 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), FAM127A (Affinity Capture-MS), VPS52 (Affinity Capture-MS), SLC25A16 (Affinity Capture-MS), DCTN6 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), SLC25A30 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), DCTN3 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), C4BPB (Reconstituted Complex), C4BPB (Protein-peptide)

ESM2 similar proteins: O08569, O62837, O88174, P02749, P04003, P05160, P08607, P14151, P15529, P16109, P16581, P17690, P19070, P20023, P20851, P26644, P27113, P30836, P33703, P33730, P68638, P68639, P70105, P79138, P98105, P98107, P98131, Q00690, Q01102, Q01339, Q03472, Q07968, Q22328, Q28065, Q28768, Q5R4D0, Q60401, Q60736, Q61475, Q61476

Diamond homologs: A0A1D5NSM8, A2AVA0, O02839, O08569, O19124, O62685, O62837, O88174, P02749, P04003, P08607, P0C6B8, P15529, P17927, P19070, P20023, P20851, P68638, P68639, P70105, P79138, Q01016, Q03472, Q09101, Q22328, Q2HRD4, Q2VPA4, Q4LDE5, Q501P1, Q53RD9, Q5R4D0, Q60401, Q60736, Q61475, Q61476, Q63135, Q63514, Q64735, Q6VE48, Q8HYX8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

56 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	7
Benign	23

Top pathogenic / likely-pathogenic (0)

SpliceAI

782 predictions. Top by Δscore:

Variant	Effect	Δscore
1:207088942:GACAG:G	donor_gain	1.0000
1:207090306:A:AG	acceptor_gain	1.0000
1:207090307:G:GG	acceptor_gain	1.0000
1:207090307:GC:G	acceptor_gain	1.0000
1:207090307:GCA:G	acceptor_gain	1.0000
1:207090307:GCAGA:G	acceptor_gain	1.0000
1:207090365:TGG:T	donor_gain	1.0000
1:207090477:CCGCT:C	donor_gain	1.0000
1:207090478:CGCT:C	donor_gain	1.0000
1:207090479:GCT:G	donor_gain	1.0000
1:207090479:GCTG:G	donor_gain	1.0000
1:207090480:CT:C	donor_gain	1.0000
1:207090481:TGT:T	donor_loss	1.0000
1:207090482:G:GA	donor_loss	1.0000
1:207090482:G:GG	donor_gain	1.0000
1:207090483:T:TC	donor_loss	1.0000
1:207090484:A:AT	donor_loss	1.0000
1:207090486:G:GG	donor_gain	1.0000
1:207090487:T:G	donor_gain	1.0000
1:207091818:GTA:G	donor_gain	1.0000
1:207098269:G:GG	donor_gain	1.0000
1:207099787:A:AG	acceptor_gain	1.0000
1:207099787:AGCTT:A	acceptor_gain	1.0000
1:207099788:G:GT	acceptor_gain	1.0000
1:207099788:GC:G	acceptor_gain	1.0000
1:207099788:GCT:G	acceptor_gain	1.0000
1:207099788:GCTT:G	acceptor_gain	1.0000
1:207099788:GCTTG:G	acceptor_gain	1.0000
1:207088944:CAG:C	donor_loss	0.9900
1:207088945:AG:A	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000026195 (1:207090575 G>A), RS1000154828 (1:207097644 T>G), RS1000257058 (1:207090817 A>G), RS1000419714 (1:207088095 C>T), RS1000751574 (1:207088482 T>C), RS1000856023 (1:207093578 C>G), RS1001053280 (1:207099821 A>C), RS1001096961 (1:207095867 C>T), RS1001114847 (1:207099867 A>G), RS1001298864 (1:207089744 A>G), RS1001527094 (1:207096064 A>G), RS1002186641 (1:207087346 C>T), RS1002216064 (1:207087682 T>C), RS1002376898 (1:207094254 T>C,G), RS1002398684 (1:207100121 G>T)

Disease associations

OMIM: gene MIM:120831 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000621_1	C4b binding protein levels	4.000000e-10
GCST008162_36	Hip circumference	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004572	C4BP measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
ethinyl estradiol-desogestrel combination	decreases expression, increases reaction	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Cholic Acids	affects cotreatment, affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Ethinyl Estradiol	affects cotreatment, decreases expression, decreases reaction	1
Fluorouracil	affects expression	1
Quercetin	decreases expression	1
Silicon Dioxide	increases expression	1
Triclosan	increases expression	1
Valproic Acid	decreases expression	1
Zinc	affects binding	1
1-Naphthylisothiocyanate	affects cotreatment, affects expression	1
Levonorgestrel	affects cotreatment, decreases expression, decreases reaction	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.