C3

Protein identityUniProt · HPA

UniProt accession

P01024

Gene

C3

Ensembl

ENSG00000125730

Chromosome

19

Canonical length

1663 aa

Protein class

Candidate cardiovascular disease genes, 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

Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients. [provided by RefSeq, Nov 2015]

Canonical amino-acid sequenceUniProt

1663 residues, UniProt reviewed canonical sequence.

>P01024|C3
     1  MGPTSGPSLL LLLLTHLPLA LGSPMYSIIT PNILRLESEE TMVLEAHDAQ GDVPVTVTVH
    61  DFPGKKLVLS SEKTVLTPAT NHMGNVTFTI PANREFKSEK GRNKFVTVQA TFGTQVVEKV
   121  VLVSLQSGYL FIQTDKTIYT PGSTVLYRIF TVNHKLLPVG RTVMVNIENP EGIPVKQDSL
   181  SSQNQLGVLP LSWDIPELVN MGQWKIRAYY ENSPQQVFST EFEVKEYVLP SFEVIVEPTE
   241  KFYYIYNEKG LEVTITARFL YGKKVEGTAF VIFGIQDGEQ RISLPESLKR IPIEDGSGEV
   301  VLSRKVLLDG VQNPRAEDLV GKSLYVSATV ILHSGSDMVQ AERSGIPIVT SPYQIHFTKT
   361  PKYFKPGMPF DLMVFVTNPD GSPAYRVPVA VQGEDTVQSL TQGDGVAKLS INTHPSQKPL
   421  SITVRTKKQE LSEAEQATRT MQALPYSTVG NSNNYLHLSV LRTELRPGET LNVNFLLRMD
   481  RAHEAKIRYY TYLIMNKGRL LKAGRQVREP GQDLVVLPLS ITTDFIPSFR LVAYYTLIGA
   541  SGQREVVADS VWVDVKDSCV GSLVVKSGQS EDRQPVPGQQ MTLKIEGDHG ARVVLVAVDK
   601  GVFVLNKKNK LTQSKIWDVV EKADIGCTPG SGKDYAGVFS DAGLTFTSSS GQQTAQRAEL
   661  QCPQPAARRR RSVQLTEKRM DKVGKYPKEL RKCCEDGMRE NPMRFSCQRR TRFISLGEAC
   721  KKVFLDCCNY ITELRRQHAR ASHLGLARSN LDEDIIAEEN IVSRSEFPES WLWNVEDLKE
   781  PPKNGISTKL MNIFLKDSIT TWEILAVSMS DKKGICVADP FEVTVMQDFF IDLRLPYSVV
   841  RNEQVEIRAV LYNYRQNQEL KVRVELLHNP AFCSLATTKR RHQQTVTIPP KSSLSVPYVI
   901  VPLKTGLQEV EVKAAVYHHF ISDGVRKSLK VVPEGIRMNK TVAVRTLDPE RLGREGVQKE
   961  DIPPADLSDQ VPDTESETRI LLQGTPVAQM TEDAVDAERL KHLIVTPSGC GEQNMIGMTP
  1021  TVIAVHYLDE TEQWEKFGLE KRQGALELIK KGYTQQLAFR QPSSAFAAFV KRAPSTWLTA
  1081  YVVKVFSLAV NLIAIDSQVL CGAVKWLILE KQKPDGVFQE DAPVIHQEMI GGLRNNNEKD
  1141  MALTAFVLIS LQEAKDICEE QVNSLPGSIT KAGDFLEANY MNLQRSYTVA IAGYALAQMG
  1201  RLKGPLLNKF LTTAKDKNRW EDPGKQLYNV EATSYALLAL LQLKDFDFVP PVVRWLNEQR
  1261  YYGGGYGSTQ ATFMVFQALA QYQKDAPDHQ ELNLDVSLQL PSRSSKITHR IHWESASLLR
  1321  SEETKENEGF TVTAEGKGQG TLSVVTMYHA KAKDQLTCNK FDLKVTIKPA PETEKRPQDA
  1381  KNTMILEICT RYRGDQDATM SILDISMMTG FAPDTDDLKQ LANGVDRYIS KYELDKAFSD
  1441  RNTLIIYLDK VSHSEDDCLA FKVHQYFNVE LIQPGAVKVY AYYNLEESCT RFYHPEKEDG
  1501  KLNKLCRDEL CRCAEENCFI QKSDDKVTLE ERLDKACEPG VDYVYKTRLV KVQLSNDFDE
  1561  YIMAIEQTIK SGSDEVQVGQ QRTFISPIKC REALKLEEKK HYLMWGLSSD FWGEKPNLSY
  1621  IIGKDTWVEH WPEEDECQDE ENQKQCQDLG AFTESMVVFG CPN

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against C3 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)

0.24

Highest tissue expression

5,062 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about C3.

Disease | AllUniProt

Conditions C3 is implicated in, by any mechanism.

• Complement component 3 deficiency (C3D) MIM:613779
• Macular degeneration, age-related, 9 (ARMD9) MIM:611378
• Hemolytic uremic syndrome, atypical, 5 (AHUS5) MIM:612925

Disease | GeneticClinVar

78 pathogenic / likely-pathogenic of 1,873 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Complement component 3 deficiency
• Atypical hemolytic-uremic syndrome with C3 anomaly
• Age related macular degeneration 9
• Atypical hemolytic-uremic syndrome
• C3 glomerulonephritis

Disease | ImmuneIEDB

Conditions an epitope on C3 was assayed in.

• rheumatoid arthritis B cell

Disease | AutoantibodyPubMed

Conditions in which antibodies against C3 are reported. Each links to that disease's full target list.

• Lupus Erythematosus, Systemic 7
• Glomerulonephritis 4
• Lupus Nephritis 4

ReferencesPubMed · IEDB

Publications for C3 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)

0.31

gnomAD pLI

0.9

gnomAD missense Z

2.75

DepMap mean gene effect

0

DepMap dependency class

none

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• amyloid-beta clearance
• B cell activation
• complement activation
• complement activation, alternative pathway
• complement activation, classical pathway
• complement activation, GZMK pathway
• complement receptor mediated signaling pathway
• complement-dependent cytotoxicity
• complement-mediated synapse pruning
• fatty acid metabolic process
• G protein-coupled receptor signaling pathway
• immune response
• inflammatory response
• neuron remodeling
• oviduct epithelium development
• positive regulation of activation of membrane attack complex
• positive regulation of angiogenesis
• positive regulation of apoptotic cell clearance
• positive regulation of D-glucose transmembrane transport
• positive regulation of G protein-coupled receptor signaling pathway
• positive regulation of lipid storage
• positive regulation of phagocytosis, engulfment
• positive regulation of protein phosphorylation
• positive regulation of receptor-mediated endocytosis
• positive regulation of type IIa hypersensitivity
• positive regulation of vascular endothelial growth factor production
• regulation of triglyceride biosynthetic process
• response to bacterium
• signal transduction
• vertebrate eye-specific patterning

Molecular functions

• endopeptidase inhibitor activity
• receptor ligand activity
• signaling receptor binding
• C5L2 anaphylatoxin chemotactic receptor binding

Cellular components

• azurophil granule lumen
• blood microparticle
• cell surface
• endoplasmic reticulum lumen
• extracellular exosome
• extracellular region
• extracellular space
• plasma membrane
• protein-containing complex
• secretory granule lumen

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
• Complement C3/4/5, macroglobulin domain MG1
• Macroglobulin domain MG3
• Alpha-macroglobulin-like, thiol-ester bond-forming region
• Alpha-2-macroglobulin/Complement system
• 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 MG1
• Macroglobulin domain MG3
• Complement C3-like, NTR domain
• Complement component 3, CUB domain, second segment
• Complement component 3, CUB domain, first segment
• Complement component 3, CUB domain, second segment
• Complement component 3, CUB domain, first segment

KeywordsUniProt

• Age-related macular degeneration
• Cleavage on pair of basic residues
• Complement alternate pathway
• Complement pathway
• Disulfide bond
• Fatty acid metabolism
• Glycoprotein
• Hemolytic uremic syndrome
• Immunity
• Inflammatory response
• Innate immunity
• Lipid metabolism
• Phosphoprotein
• Secreted
• Signal
• Thioester bond

InteractionsUniProt · HPA

Protein binding partners of C3 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• CFH
• CFP
• CR1
• CR2