C4B

Protein identityUniProt · HPA

UniProt accession

P0C0L5

Gene

C4B

Ensembl

ENSG00000224389

Chromosome

6

Canonical length

1744 aa

Protein class

Blood group antigen proteins, Disease related genes, FDA approved drug targets, Human disease related genes, Plasma proteins, Predicted intracellular proteins, Predicted secreted proteins

Secretome location

Secreted to blood

OverviewNCBI Gene

This gene encodes the basic form of complement factor 4, and together with the C4A gene, is 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. [provided by RefSeq, May 2020]

Canonical amino-acid sequenceUniProt

1744 residues, UniProt reviewed canonical sequence.

>P0C0L5|C4B
     1  MRLLWGLIWA SSFFTLSLQK PRLLLFSPSV VHLGVPLSVG VQLQDVPRGQ VVKGSVFLRN
    61  PSRNNVPCSP KVDFTLSSER DFALLSLQVP LKDAKSCGLH QLLRGPEVQL VAHSPWLKDS
   121  LSRTTNIQGI NLLFSSRRGH LFLQTDQPIY NPGQRVRYRV FALDQKMRPS TDTITVMVEN
   181  SHGLRVRKKE VYMPSSIFQD DFVIPDISEP GTWKISARFS DGLESNSSTQ FEVKKYVLPN
   241  FEVKITPGKP YILTVPGHLD EMQLDIQARY IYGKPVQGVA YVRFGLLDED GKKTFFRGLE
   301  SQTKLVNGQS HISLSKAEFQ DALEKLNMGI TDLQGLRLYV AAAIIESPGG EMEEAELTSW
   361  YFVSSPFSLD LSKTKRHLVP GAPFLLQALV REMSGSPASG IPVKVSATVS SPGSVPEVQD
   421  IQQNTDGSGQ VSIPIIIPQT ISELQLSVSA GSPHPAIARL TVAAPPSGGP GFLSIERPDS
   481  RPPRVGDTLN LNLRAVGSGA TFSHYYYMIL SRGQIVFMNR EPKRTLTSVS VFVDHHLAPS
   541  FYFVAFYYHG DHPVANSLRV DVQAGACEGK LELSVDGAKQ YRNGESVKLH LETDSLALVA
   601  LGALDTALYA AGSKSHKPLN MGKVFEAMNS YDLGCGPGGG DSALQVFQAA GLAFSDGDQW
   661  TLSRKRLSCP KEKTTRKKRN VNFQKAINEK LGQYASPTAK RCCQDGVTRL PMMRSCEQRA
   721  ARVQQPDCRE PFLSCCQFAE SLRKKSRDKG QAGLQRALEI LQEEDLIDED DIPVRSFFPE
   781  NWLWRVETVD RFQILTLWLP DSLTTWEIHG LSLSKTKGLC VATPVQLRVF REFHLHLRLP
   841  MSVRRFEQLE LRPVLYNYLD KNLTVSVHVS PVEGLCLAGG GGLAQQVLVP AGSARPVAFS
   901  VVPTAATAVS LKVVARGSFE FPVGDAVSKV LQIEKEGAIH REELVYELNP LDHRGRTLEI
   961  PGNSDPNMIP DGDFNSYVRV TASDPLDTLG SEGALSPGGV ASLLRLPRGC GEQTMIYLAP
  1021  TLAASRYLDK TEQWSTLPPE TKDHAVDLIQ KGYMRIQQFR KADGSYAAWL SRGSSTWLTA
  1081  FVLKVLSLAQ EQVGGSPEKL QETSNWLLSQ QQADGSFQDL SPVIHRSMQG GLVGNDETVA
  1141  LTAFVTIALH HGLAVFQDEG AEPLKQRVEA SISKASSFLG EKASAGLLGA HAAAITAYAL
  1201  TLTKAPADLR GVAHNNLMAM AQETGDNLYW GSVTGSQSNA VSPTPAPRNP SDPMPQAPAL
  1261  WIETTAYALL HLLLHEGKAE MADQAAAWLT RQGSFQGGFR STQDTVIALD ALSAYWIASH
  1321  TTEERGLNVT LSSTGRNGFK SHALQLNNRQ IRGLEEELQF SLGSKINVKV GGNSKGTLKV
  1381  LRTYNVLDMK NTTCQDLQIE VTVKGHVEYT MEANEDYEDY EYDELPAKDD PDAPLQPVTP
  1441  LQLFEGRRNR RRREAPKVVE EQESRVHYTV CIWRNGKVGL SGMAIADVTL LSGFHALRAD
  1501  LEKLTSLSDR YVSHFETEGP HVLLYFDSVP TSRECVGFEA VQEVPVGLVQ PASATLYDYY
  1561  NPERRCSVFY GAPSKSRLLA TLCSAEVCQC AEGKCPRQRR ALERGLQDED GYRMKFACYY
  1621  PRVEYGFQVK VLREDSRAAF RLFETKITQV LHFTKDVKAA ANQMRNFLVR ASCRLRLEPG
  1681  KEYLIMGLDG ATYDLEGHPQ YLLDSNSWIE EMPSERLCRS TRQRAACAQL NDFLQEYGTQ
  1741  GCQV

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against C4B can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.26

Highest tissue expression

262 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about C4B.

Disease | AllUniProt

Conditions C4B is implicated in, by any mechanism.

• Systemic lupus erythematosus (SLE) MIM:152700
• Complement component 4B deficiency (C4BD) MIM:614379

Disease | GeneticClinVar

3 pathogenic / likely-pathogenic of 92 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Complement component 4b deficiency

Disease | ImmuneIEDB

Conditions an epitope on C4B was assayed in.

• rheumatoid arthritis B cell

ReferencesPubMed · IEDB

Publications for C4B from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. IEDB — curated epitope assays from the Immune Epitope Database (Vita et al., Nucleic Acids Research 2019). Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.41

gnomAD pLI

0.83

gnomAD missense Z

2.02

OntologyGO

Biological processes

• complement activation
• complement activation, classical pathway
• complement activation, GZMK pathway
• detection of molecule of bacterial origin
• inflammatory response
• opsonization
• positive regulation of apoptotic cell clearance

Molecular functions

• carbohydrate binding
• complement binding
• endopeptidase inhibitor activity

Cellular components

• axon
• blood microparticle
• cell surface
• dendrite
• extracellular exosome
• extracellular region
• extracellular space
• plasma membrane
• symbiont cell surface
• synapse

Protein domainsUniProt · Pfam · InterPro

• Anaphylatoxin/fibulin
• Netrin domain
• Alpha-2-macroglobulin
• Anaphylatoxin, complement system domain
• Macroglobulin domain
• Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid
• Tissue inhibitor of metalloproteinases-like, OB-fold
• Alpha-macroglobulin, receptor-binding
• Alpha-2-macroglobulin, bait region domain
• Alpha-macroglobulin-like, TED domain
• Immunoglobulin-like fold
• Anaphylatoxin, complement system
• Netrin module, non-TIMP type
• Alpha-2-macroglobulin, conserved site
• Alpha-macroglobulin, receptor-binding domain superfamily
• Macroglobulin domain MG4
• Macroglobulin domain MG3
• Alpha-macroglobulin-like, thiol-ester bond-forming region
• Complement C4, MG1 domain
• Alpha-2-macroglobulin/Complement system
• Complement C4A/B, CUB C-terminal domain
• Alpha-2-macroglobulin family
• UNC-6/NTR/C345C module
• Anaphylotoxin-like domain
• MG2 domain
• A-macroglobulin receptor binding domain
• A-macroglobulin TED domain
• Alpha-2-macroglobulin bait region domain
• Macroglobulin domain MG4
• Macroglobulin domain MG3
• Complement C4, MG1 domain
• Complement C4A/B CUB C-terminal domain

KeywordsUniProt

• Blood group antigen
• Cell projection
• Cleavage on pair of basic residues
• Complement pathway
• Disulfide bond
• Glycoprotein
• Immunity
• Inflammatory response
• Innate immunity
• Phosphoprotein
• Secreted
• Signal
• Sulfation
• Synapse
• Systemic lupus erythematosus
• Thioester bond

InteractionsUniProt · HPA

Protein binding partners of C4B in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• CR1