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Protein

Complement C4-A

Gene

C4A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Non-enzymatic component of 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.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei1125Responsible for effective binding to form amide bonds with immune aggregates or protein antigens1

GO - Molecular functioni

GO - Biological processi

  • complement activation Source: BHF-UCL
  • complement activation, classical pathway Source: UniProtKB-KW
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • positive regulation of apoptotic cell clearance Source: BHF-UCL
  • regulation of complement activation Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Blood group antigen

Keywords - Biological processi

Complement pathway, Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-HSA-166663. Initial triggering of complement.
R-HSA-174577. Activation of C3 and C5.
R-HSA-977606. Regulation of Complement cascade.
SABIO-RKP0C0L4.

Names & Taxonomyi

Protein namesi
Recommended name:
Complement C4-A
Alternative name(s):
Acidic complement C4
C3 and PZP-like alpha-2-macroglobulin domain-containing protein 2
Cleaved into the following 6 chains:
Gene namesi
Name:C4A
Synonyms:CO4, CPAMD2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:1323. C4A.

Subcellular locationi

GO - Cellular componenti

  • axon Source: UniProtKB
  • blood microparticle Source: UniProtKB
  • cell junction Source: UniProtKB-KW
  • dendrite Source: UniProtKB
  • extracellular exosome Source: UniProtKB
  • extracellular region Source: Reactome
  • extracellular space Source: UniProtKB
  • neuronal cell body Source: UniProtKB
  • plasma membrane Source: Reactome
  • synapse Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell projection, Secreted, Synapse

Pathology & Biotechi

Involvement in diseasei

Complement component 4A deficiency (C4AD)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis.
See also OMIM:614380
Systemic lupus erythematosus (SLE)2 Publications
Disease susceptibility is associated with variations 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.
Disease descriptionA 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.
See also OMIM:152700

Keywords - Diseasei

Disease mutation, Systemic lupus erythematosus

Organism-specific databases

DisGeNETi100293534.
720.
721.
MalaCardsiC4A.
MIMi120790. phenotype.
152700. phenotype.
614374. phenotype.
614380. phenotype.
OpenTargetsiENSG00000244731.
Orphaneti117. Behcet disease.
169147. Immunodeficiency due to an early component of complement deficiency.
536. Systemic lupus erythematosus.
PharmGKBiPA25903.
PA25904.

Chemistry databases

DrugBankiDB00028. Intravenous Immunoglobulin.

Polymorphism and mutation databases

BioMutaiC4A.
DMDMi476007827.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Add BLAST19
ChainiPRO_000000596620 – 675Complement C4 beta chainAdd BLAST656
PropeptideiPRO_0000005967676 – 6791 Publication4
ChainiPRO_0000005968680 – 1446Complement C4-A alpha chainAdd BLAST767
ChainiPRO_0000005969680 – 756C4a anaphylatoxinAdd BLAST77
ChainiPRO_0000005970757 – 1446C4b-AAdd BLAST690
ChainiPRO_0000042698957 – 1336C4d-AAdd BLAST380
PropeptideiPRO_00000059711447 – 14537
ChainiPRO_00000059721454 – 1744Complement C4 gamma chainAdd BLAST291

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi226N-linked (GlcNAc...)3 Publications1
Disulfide bondi702 ↔ 728By similarity
Disulfide bondi703 ↔ 735By similarity
Disulfide bondi716 ↔ 736By similarity
Glycosylationi862N-linked (GlcNAc...)1 Publication1
Modified residuei918Phosphoserine; by FAM20C1 Publication1
Cross-linki1010 ↔ 1013Isoglutamyl cysteine thioester (Cys-Gln)
Glycosylationi1244O-linked (GalNAc...)1 Publication1
Glycosylationi1328N-linked (GlcNAc...) (complex)4 Publications1
Glycosylationi1391N-linked (GlcNAc...)3 Publications1
Modified residuei1417Sulfotyrosine1 Publication1
Modified residuei1420Sulfotyrosine1 Publication1
Modified residuei1422Sulfotyrosine1 Publication1
Disulfide bondi1595 ↔ 1673By similarity
Disulfide bondi1618 ↔ 1742By similarity

Post-translational modificationi

Prior to secretion, the single-chain precursor is enzymatically cleaved to yield non-identical chains alpha, beta and gamma. During activation, the alpha chain is cleaved by C1 into C4a and C4b, and C4b stays linked to the beta and gamma chains. 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.
N- and O-glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.8 Publications

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Phosphoprotein, Sulfation, Thioester bond

Proteomic databases

EPDiP0C0L4.
MaxQBiP0C0L4.
PaxDbiP0C0L4.
PeptideAtlasiP0C0L4.
PRIDEiP0C0L4.

PTM databases

iPTMnetiP0C0L4.
PhosphoSitePlusiP0C0L4.
UniCarbKBiP0C0L4.

Miscellaneous databases

PMAP-CutDBB0QZR6.

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiENSG00000206340.
GenevisibleiP0C0L4. HS.

Organism-specific databases

HPAiCAB009811.
CAB032603.
HPA046356.
HPA048287.
HPA050103.

Interactioni

Subunit structurei

Circulates in blood as a disulfide-linked trimer of an alpha, beta and gamma chain.

GO - Molecular functioni

  • complement component C1q binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi107181. 23 interactors.
107182. 2 interactors.
IntActiP0C0L4. 11 interactors.
STRINGi9606.ENSP00000396688.

Structurei

Secondary structure

11744
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi22 – 32Combined sources11
Beta strandi37 – 45Combined sources9
Beta strandi51 – 59Combined sources9
Beta strandi67 – 69Combined sources3
Beta strandi72 – 77Combined sources6
Beta strandi82 – 87Combined sources6
Helixi91 – 97Combined sources7
Helixi99 – 101Combined sources3
Beta strandi107 – 113Combined sources7
Helixi116 – 119Combined sources4
Beta strandi126 – 135Combined sources10
Beta strandi139 – 146Combined sources8
Beta strandi148 – 150Combined sources3
Beta strandi155 – 163Combined sources9
Beta strandi167 – 169Combined sources3
Beta strandi174 – 179Combined sources6
Beta strandi181 – 183Combined sources3
Beta strandi185 – 191Combined sources7
Beta strandi194 – 203Combined sources10
Beta strandi210 – 221Combined sources12
Beta strandi228 – 233Combined sources6
Beta strandi240 – 253Combined sources14
Beta strandi262 – 270Combined sources9
Beta strandi278 – 287Combined sources10
Beta strandi289 – 291Combined sources3
Beta strandi293 – 295Combined sources3
Beta strandi301 – 304Combined sources4
Beta strandi309 – 314Combined sources6
Helixi316 – 325Combined sources10
Helixi330 – 332Combined sources3
Beta strandi337 – 346Combined sources10
Turni347 – 349Combined sources3
Beta strandi352 – 357Combined sources6
Beta strandi361 – 364Combined sources4
Beta strandi366 – 370Combined sources5
Beta strandi372 – 374Combined sources3
Beta strandi382 – 392Combined sources11
Beta strandi395 – 397Combined sources3
Beta strandi402 – 409Combined sources8
Beta strandi412 – 414Combined sources3
Beta strandi417 – 424Combined sources8
Beta strandi430 – 436Combined sources7
Beta strandi442 – 450Combined sources9
Beta strandi452 – 454Combined sources3
Beta strandi456 – 463Combined sources8
Beta strandi472 – 476Combined sources5
Beta strandi488 – 498Combined sources11
Beta strandi504 – 511Combined sources8
Beta strandi514 – 522Combined sources9
Beta strandi527 – 532Combined sources6
Turni535 – 537Combined sources3
Beta strandi539 – 549Combined sources11
Beta strandi552 – 561Combined sources10
Beta strandi571 – 575Combined sources5
Beta strandi586 – 605Combined sources20
Helixi607 – 611Combined sources5
Helixi621 – 628Combined sources8
Helixi629 – 631Combined sources3
Helixi643 – 650Combined sources8
Beta strandi652 – 655Combined sources4
Beta strandi657 – 660Combined sources4
Turni666 – 668Combined sources3
Beta strandi780 – 782Combined sources3
Beta strandi786 – 798Combined sources13
Beta strandi804 – 814Combined sources11
Turni815 – 817Combined sources3
Beta strandi818 – 821Combined sources4
Beta strandi825 – 829Combined sources5
Beta strandi832 – 836Combined sources5
Beta strandi849 – 851Combined sources3
Beta strandi854 – 857Combined sources4
Beta strandi859 – 861Combined sources3
Beta strandi863 – 869Combined sources7
Beta strandi875 – 877Combined sources3
Helixi878 – 880Combined sources3
Beta strandi885 – 889Combined sources5
Beta strandi893 – 896Combined sources4
Beta strandi899 – 903Combined sources5
Beta strandi906 – 921Combined sources16
Beta strandi924 – 934Combined sources11
Beta strandi936 – 948Combined sources13
Beta strandi951 – 961Combined sources11
Beta strandi974 – 982Combined sources9
Helixi997 – 1001Combined sources5
Helixi1011 – 1030Combined sources20
Helixi1034 – 1036Combined sources3
Helixi1041 – 1057Combined sources17
Turni1062 – 1064Combined sources3
Helixi1076 – 1089Combined sources14
Helixi1090 – 1092Combined sources3
Helixi1097 – 1107Combined sources11
Helixi1108 – 1110Combined sources3
Beta strandi1113 – 1115Combined sources3
Helixi1126 – 1132Combined sources7
Helixi1137 – 1153Combined sources17
Turni1158 – 1161Combined sources4
Helixi1162 – 1185Combined sources24
Helixi1190 – 1202Combined sources13
Helixi1207 – 1218Combined sources12
Beta strandi1225 – 1228Combined sources4
Helixi1259 – 1275Combined sources17
Helixi1280 – 1292Combined sources13
Helixi1294 – 1297Combined sources4
Helixi1302 – 1319Combined sources18
Beta strandi1327 – 1335Combined sources9
Beta strandi1338 – 1346Combined sources9
Beta strandi1348 – 1350Combined sources3
Beta strandi1356 – 1359Combined sources4
Beta strandi1364 – 1373Combined sources10
Beta strandi1376 – 1386Combined sources11
Beta strandi1395 – 1405Combined sources11
Beta strandi1409 – 1411Combined sources3
Beta strandi1465 – 1475Combined sources11
Beta strandi1484 – 1489Combined sources6
Beta strandi1494 – 1496Combined sources3
Helixi1498 – 1506Combined sources9
Beta strandi1511 – 1518Combined sources8
Beta strandi1521 – 1527Combined sources7
Beta strandi1534 – 1544Combined sources11
Beta strandi1552 – 1560Combined sources9
Beta strandi1564 – 1570Combined sources7
Beta strandi1573 – 1575Combined sources3
Beta strandi1581 – 1584Combined sources4
Beta strandi1587 – 1590Combined sources4
Helixi1613 – 1618Combined sources6
Beta strandi1624 – 1637Combined sources14
Beta strandi1640 – 1652Combined sources13
Beta strandi1664 – 1670Combined sources7
Beta strandi1681 – 1687Combined sources7
Beta strandi1708 – 1711Combined sources4
Helixi1716 – 1719Combined sources4
Helixi1721 – 1723Combined sources3
Helixi1726 – 1740Combined sources15

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1HZFX-ray2.30A957-1323[»]
4FXGX-ray3.75A/D20-675[»]
B/E680-1446[»]
C/F1454-1744[»]
4FXKX-ray3.60A20-675[»]
B680-1446[»]
C1454-1744[»]
4XAMX-ray4.20C/E757-1446[»]
D/F1454-1744[»]
5JPMX-ray3.75A/D20-675[»]
B/E680-1446[»]
C/F1454-1744[»]
5JPNX-ray3.60A20-675[»]
B680-1446[»]
C1455-1744[»]
5JTWX-ray3.50A/D20-675[»]
B/E757-1446[»]
C/F1454-1744[»]
ProteinModelPortaliP0C0L4.
SMRiP0C0L4.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP0C0L4.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini702 – 736Anaphylatoxin-likePROSITE-ProRule annotationAdd BLAST35
Domaini1595 – 1742NTRPROSITE-ProRule annotationAdd BLAST148

Sequence similaritiesi

Contains 1 anaphylatoxin-like domain.PROSITE-ProRule annotation
Contains 1 NTR domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG1366. Eukaryota.
ENOG410XRED. LUCA.
GeneTreeiENSGT00760000118982.
HOGENOMiHOG000290712.
HOVERGENiHBG107123.
InParanoidiP0C0L4.
KOiK03989.
OMAiDWFDIRS.
OrthoDBiEOG091G00FL.
PhylomeDBiP0C0L4.
TreeFamiTF313285.

Family and domain databases

Gene3Di1.20.91.20. 1 hit.
1.50.10.20. 1 hit.
2.60.40.690. 1 hit.
InterProiIPR009048. A-macroglobulin_rcpt-bd.
IPR011626. A2M_comp.
IPR002890. A2M_N.
IPR011625. A2M_N_2.
IPR000020. Anaphylatoxin/fibulin.
IPR018081. Anaphylatoxin_comp_syst.
IPR001840. Anaphylatoxn_comp_syst_dom.
IPR001599. Macroglobln_a2.
IPR019742. MacrogloblnA2_CS.
IPR019565. MacrogloblnA2_thiol-ester-bond.
IPR001134. Netrin_domain.
IPR018933. Netrin_module_non-TIMP.
IPR008930. Terpenoid_cyclase/PrenylTrfase.
IPR008993. TIMP-like_OB-fold.
[Graphical view]
PfamiPF00207. A2M. 1 hit.
PF07678. A2M_comp. 1 hit.
PF01835. A2M_N. 1 hit.
PF07703. A2M_N_2. 1 hit.
PF07677. A2M_recep. 1 hit.
PF01821. ANATO. 1 hit.
PF01759. NTR. 1 hit.
PF10569. Thiol-ester_cl. 1 hit.
[Graphical view]
PRINTSiPR00004. ANAPHYLATOXN.
SMARTiSM01360. A2M. 1 hit.
SM01359. A2M_N_2. 1 hit.
SM01361. A2M_recep. 1 hit.
SM00104. ANATO. 1 hit.
SM00643. C345C. 1 hit.
[Graphical view]
SUPFAMiSSF47686. SSF47686. 1 hit.
SSF48239. SSF48239. 1 hit.
SSF49410. SSF49410. 1 hit.
SSF50242. SSF50242. 1 hit.
PROSITEiPS00477. ALPHA_2_MACROGLOBULIN. 1 hit.
PS01177. ANAPHYLATOXIN_1. 1 hit.
PS01178. ANAPHYLATOXIN_2. 1 hit.
PS50189. NTR. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P0C0L4-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MRLLWGLIWA SSFFTLSLQK PRLLLFSPSV VHLGVPLSVG VQLQDVPRGQ
60 70 80 90 100
VVKGSVFLRN PSRNNVPCSP KVDFTLSSER DFALLSLQVP LKDAKSCGLH
110 120 130 140 150
QLLRGPEVQL VAHSPWLKDS LSRTTNIQGI NLLFSSRRGH LFLQTDQPIY
160 170 180 190 200
NPGQRVRYRV FALDQKMRPS TDTITVMVEN SHGLRVRKKE VYMPSSIFQD
210 220 230 240 250
DFVIPDISEP GTWKISARFS DGLESNSSTQ FEVKKYVLPN FEVKITPGKP
260 270 280 290 300
YILTVPGHLD EMQLDIQARY IYGKPVQGVA YVRFGLLDED GKKTFFRGLE
310 320 330 340 350
SQTKLVNGQS HISLSKAEFQ DALEKLNMGI TDLQGLRLYV AAAIIESPGG
360 370 380 390 400
EMEEAELTSW YFVSSPFSLD LSKTKRHLVP GAPFLLQALV REMSGSPASG
410 420 430 440 450
IPVKVSATVS SPGSVPEVQD IQQNTDGSGQ VSIPIIIPQT ISELQLSVSA
460 470 480 490 500
GSPHPAIARL TVAAPPSGGP GFLSIERPDS RPPRVGDTLN LNLRAVGSGA
510 520 530 540 550
TFSHYYYMIL SRGQIVFMNR EPKRTLTSVS VFVDHHLAPS FYFVAFYYHG
560 570 580 590 600
DHPVANSLRV DVQAGACEGK LELSVDGAKQ YRNGESVKLH LETDSLALVA
610 620 630 640 650
LGALDTALYA AGSKSHKPLN MGKVFEAMNS YDLGCGPGGG DSALQVFQAA
660 670 680 690 700
GLAFSDGDQW TLSRKRLSCP KEKTTRKKRN VNFQKAINEK LGQYASPTAK
710 720 730 740 750
RCCQDGVTRL PMMRSCEQRA ARVQQPDCRE PFLSCCQFAE SLRKKSRDKG
760 770 780 790 800
QAGLQRALEI LQEEDLIDED DIPVRSFFPE NWLWRVETVD RFQILTLWLP
810 820 830 840 850
DSLTTWEIHG LSLSKTKGLC VATPVQLRVF REFHLHLRLP MSVRRFEQLE
860 870 880 890 900
LRPVLYNYLD KNLTVSVHVS PVEGLCLAGG GGLAQQVLVP AGSARPVAFS
910 920 930 940 950
VVPTAAAAVS LKVVARGSFE FPVGDAVSKV LQIEKEGAIH REELVYELNP
960 970 980 990 1000
LDHRGRTLEI PGNSDPNMIP DGDFNSYVRV TASDPLDTLG SEGALSPGGV
1010 1020 1030 1040 1050
ASLLRLPRGC GEQTMIYLAP TLAASRYLDK TEQWSTLPPE TKDHAVDLIQ
1060 1070 1080 1090 1100
KGYMRIQQFR KADGSYAAWL SRDSSTWLTA FVLKVLSLAQ EQVGGSPEKL
1110 1120 1130 1140 1150
QETSNWLLSQ QQADGSFQDP CPVLDRSMQG GLVGNDETVA LTAFVTIALH
1160 1170 1180 1190 1200
HGLAVFQDEG AEPLKQRVEA SISKANSFLG EKASAGLLGA HAAAITAYAL
1210 1220 1230 1240 1250
TLTKAPVDLL GVAHNNLMAM AQETGDNLYW GSVTGSQSNA VSPTPAPRNP
1260 1270 1280 1290 1300
SDPMPQAPAL WIETTAYALL HLLLHEGKAE MADQASAWLT RQGSFQGGFR
1310 1320 1330 1340 1350
STQDTVIALD ALSAYWIASH TTEERGLNVT LSSTGRNGFK SHALQLNNRQ
1360 1370 1380 1390 1400
IRGLEEELQF SLGSKINVKV GGNSKGTLKV LRTYNVLDMK NTTCQDLQIE
1410 1420 1430 1440 1450
VTVKGHVEYT MEANEDYEDY EYDELPAKDD PDAPLQPVTP LQLFEGRRNR
1460 1470 1480 1490 1500
RRREAPKVVE EQESRVHYTV CIWRNGKVGL SGMAIADVTL LSGFHALRAD
1510 1520 1530 1540 1550
LEKLTSLSDR YVSHFETEGP HVLLYFDSVP TSRECVGFEA VQEVPVGLVQ
1560 1570 1580 1590 1600
PASATLYDYY NPERRCSVFY GAPSKSRLLA TLCSAEVCQC AEGKCPRQRR
1610 1620 1630 1640 1650
ALERGLQDED GYRMKFACYY PRVEYGFQVK VLREDSRAAF RLFETKITQV
1660 1670 1680 1690 1700
LHFTKDVKAA ANQMRNFLVR ASCRLRLEPG KEYLIMGLDG ATYDLEGHPQ
1710 1720 1730 1740
YLLDSNSWIE EMPSERLCRS TRQRAACAQL NDFLQEYGTQ GCQV
Length:1,744
Mass (Da):192,785
Last modified:April 3, 2013 - v2
Checksum:i9396A4CC4DA3602C
GO
Isoform 2 (identifier: P0C0L4-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1458-1503: Missing.

Note: No experimental confirmation available.
Show »
Length:1,698
Mass (Da):187,704
Checksum:i6169C0C84E28C512
GO

Sequence cautioni

The sequence AAB59537 differs from that shown. During cDNA synthesis, the 5' end has been inverted (PubMed:3838531).1 Publication
The sequence BAE06071 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti217A → V in AAI71786 (PubMed:15489334).Curated1
Sequence conflicti643A → S in AAH63289 (PubMed:15489334).Curated1
Sequence conflicti729R → W in AAH63289 (PubMed:15489334).Curated1
Sequence conflicti1013Q → E AA sequence (PubMed:6978711).Curated1
Sequence conflicti1013Q → E AA sequence (PubMed:3696167).Curated1
Sequence conflicti1013Q → E AA sequence (PubMed:6950384).Curated1
Sequence conflicti1109 – 1110SQ → IA AA sequence (PubMed:3696167).Curated2
Sequence conflicti1182K → I in AAH63289 (PubMed:15489334).Curated1
Sequence conflicti1245P → Q in AAH63289 (PubMed:15489334).Curated1
Sequence conflicti1271H → V AA sequence (PubMed:3696167).Curated1
Sequence conflicti1271H → V AA sequence (PubMed:6832377).Curated1
Sequence conflicti1300R → V AA sequence (PubMed:3696167).Curated1
Sequence conflicti1300R → V AA sequence (PubMed:6832377).Curated1
Sequence conflicti1419 – 1421Missing in AAB59537 (PubMed:6546707).Curated3
Sequence conflicti1635D → G in AAH12372 (PubMed:15489334).Curated1
Sequence conflicti1637R → S in AAI44547 (PubMed:15489334).Curated1
Sequence conflicti1637R → S in AAI46850 (PubMed:15489334).Curated1
Sequence conflicti1678E → G in AAI71786 (PubMed:15489334).Curated1
Sequence conflicti1704D → E in AAH12372 (PubMed:15489334).Curated1

Polymorphismi

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 [MIMi: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. 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 (PubMed:11367523). C4A6 allotype is deficient in hemolytic activity. Allotype C4A13 is infrequent. Common copy-number variants of C4A and C4B affecting expression of complement component C4 in the brain have been associated with schizophrenia risk (PubMed:26814963).2 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_069154141L → V.Corresponds to variant rs9296005dbSNPEnsembl.1
Natural variantiVAR_019778347S → Y in allotype C4A3a, allotype C4A6. 3 PublicationsCorresponds to variant rs150969927dbSNPEnsembl.1
Natural variantiVAR_069155418V → A in allotype C4A4. 1 Publication1
Natural variantiVAR_001987477R → W in allotype C4A6. 1 Publication1
Natural variantiVAR_069156549H → P.1 PublicationCorresponds to variant rs2229405dbSNPEnsembl.1
Natural variantiVAR_069157564A → D.Corresponds to variant rs35277227dbSNPEnsembl.1
Natural variantiVAR_001988726P → L in allotype C4A3a. 1 Publication1
Natural variantiVAR_019779727D → N.1 Publication1
Natural variantiVAR_019780907A → T.1 PublicationCorresponds to variant rs141302872dbSNPEnsembl.1
Natural variantiVAR_0691581073D → G in allotype C4A1, allotype C4A2. 3 PublicationsCorresponds to variant rs147162052dbSNPEnsembl.1
Natural variantiVAR_0691591176N → S in allotype C4A1. 4 PublicationsCorresponds to variant rs17874654dbSNPEnsembl.1
Natural variantiVAR_0019921201T → S in allotype C4A4. 1 Publication1
Natural variantiVAR_0019931207V → A in allotype C4A1, allotype C4A13. 3 PublicationsCorresponds to variant rs28357075dbSNPEnsembl.1
Natural variantiVAR_0019941210L → R in allotype C4A1, allotype C4A13. 3 PublicationsCorresponds to variant rs28357076dbSNPEnsembl.1
Natural variantiVAR_0019951286S → A in allotype C4A1, allotype C4A3a, allotype C4A6. 6 PublicationsCorresponds to variant rs201016130dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0462521458 – 1503Missing in isoform 2. 1 PublicationAdd BLAST46

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K02403 mRNA. Translation: AAB59537.1. Sequence problems.
M59815, M59816 Genomic DNA. Translation: AAA51855.1.
L26261 Genomic DNA. Translation: AAA20121.2.
AB209989 mRNA. Translation: BAE06071.1. Different initiation.
AL645922 Genomic DNA. No translation available.
AL844853 Genomic DNA. No translation available.
AL929593 Genomic DNA. No translation available.
CR936924 Genomic DNA. No translation available.
BC012372 mRNA. Translation: AAH12372.2.
BC063289 mRNA. Translation: AAH63289.1.
BC144546 mRNA. Translation: AAI44547.1.
BC146673 mRNA. Translation: AAI46674.1.
BC146849 mRNA. Translation: AAI46850.1.
BC151204 mRNA. Translation: AAI51205.1.
BC171786 mRNA. Translation: AAI71786.1.
M14824 Genomic DNA. Translation: AAA52292.1.
X77491 Genomic DNA. Translation: CAA54627.1.
AY379925 Genomic DNA. Translation: AAR89152.1.
AY379926 Genomic DNA. Translation: AAR89153.1.
AY379927 Genomic DNA. Translation: AAR89154.1.
AY379928 Genomic DNA. Translation: AAR89155.1.
AY379929 Genomic DNA. Translation: AAR89156.1.
AY379930 Genomic DNA. Translation: AAR89157.1.
AY379931 Genomic DNA. Translation: AAR89158.1.
AY379932 Genomic DNA. Translation: AAR89159.1.
AY379933 Genomic DNA. Translation: AAR89160.1.
AY379934 Genomic DNA. Translation: AAR89161.1.
AY379935 Genomic DNA. Translation: AAR89162.1.
AY379960 Genomic DNA. Translation: AAR89164.1.
AY379962 Genomic DNA. Translation: AAR89166.1.
AY379963 Genomic DNA. Translation: AAR89167.1.
AY379964 Genomic DNA. Translation: AAR89168.1.
AY379965 Genomic DNA. Translation: AAR89169.1.
AY379966 Genomic DNA. Translation: AAR89170.1.
U77886 Genomic DNA. Translation: AAK49810.1.
V00502 mRNA. Translation: CAA23760.1.
K00830 mRNA. Translation: AAA36229.1.
CCDSiCCDS47404.1. [P0C0L4-1]
CCDS59005.1. [P0C0L4-2]
PIRiB20807.
I56095. C4HU.
RefSeqiNP_001002029.3. NM_001002029.3.
NP_001239133.1. NM_001252204.1. [P0C0L4-2]
NP_009224.2. NM_007293.2. [P0C0L4-1]
UniGeneiHs.534847.
Hs.720022.

Genome annotation databases

EnsembliENST00000383325; ENSP00000372815; ENSG00000206340.
ENST00000421274; ENSP00000388662; ENSG00000227746.
ENST00000428956; ENSP00000396688; ENSG00000244731. [P0C0L4-1]
ENST00000498271; ENSP00000420212; ENSG00000244731. [P0C0L4-2]
GeneIDi720.
721.
KEGGihsa:720.
hsa:721.
UCSCiuc011doy.3. human. [P0C0L4-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

dbRBC/BGMUT

Blood group antigen gene mutation database

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K02403 mRNA. Translation: AAB59537.1. Sequence problems.
M59815, M59816 Genomic DNA. Translation: AAA51855.1.
L26261 Genomic DNA. Translation: AAA20121.2.
AB209989 mRNA. Translation: BAE06071.1. Different initiation.
AL645922 Genomic DNA. No translation available.
AL844853 Genomic DNA. No translation available.
AL929593 Genomic DNA. No translation available.
CR936924 Genomic DNA. No translation available.
BC012372 mRNA. Translation: AAH12372.2.
BC063289 mRNA. Translation: AAH63289.1.
BC144546 mRNA. Translation: AAI44547.1.
BC146673 mRNA. Translation: AAI46674.1.
BC146849 mRNA. Translation: AAI46850.1.
BC151204 mRNA. Translation: AAI51205.1.
BC171786 mRNA. Translation: AAI71786.1.
M14824 Genomic DNA. Translation: AAA52292.1.
X77491 Genomic DNA. Translation: CAA54627.1.
AY379925 Genomic DNA. Translation: AAR89152.1.
AY379926 Genomic DNA. Translation: AAR89153.1.
AY379927 Genomic DNA. Translation: AAR89154.1.
AY379928 Genomic DNA. Translation: AAR89155.1.
AY379929 Genomic DNA. Translation: AAR89156.1.
AY379930 Genomic DNA. Translation: AAR89157.1.
AY379931 Genomic DNA. Translation: AAR89158.1.
AY379932 Genomic DNA. Translation: AAR89159.1.
AY379933 Genomic DNA. Translation: AAR89160.1.
AY379934 Genomic DNA. Translation: AAR89161.1.
AY379935 Genomic DNA. Translation: AAR89162.1.
AY379960 Genomic DNA. Translation: AAR89164.1.
AY379962 Genomic DNA. Translation: AAR89166.1.
AY379963 Genomic DNA. Translation: AAR89167.1.
AY379964 Genomic DNA. Translation: AAR89168.1.
AY379965 Genomic DNA. Translation: AAR89169.1.
AY379966 Genomic DNA. Translation: AAR89170.1.
U77886 Genomic DNA. Translation: AAK49810.1.
V00502 mRNA. Translation: CAA23760.1.
K00830 mRNA. Translation: AAA36229.1.
CCDSiCCDS47404.1. [P0C0L4-1]
CCDS59005.1. [P0C0L4-2]
PIRiB20807.
I56095. C4HU.
RefSeqiNP_001002029.3. NM_001002029.3.
NP_001239133.1. NM_001252204.1. [P0C0L4-2]
NP_009224.2. NM_007293.2. [P0C0L4-1]
UniGeneiHs.534847.
Hs.720022.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1HZFX-ray2.30A957-1323[»]
4FXGX-ray3.75A/D20-675[»]
B/E680-1446[»]
C/F1454-1744[»]
4FXKX-ray3.60A20-675[»]
B680-1446[»]
C1454-1744[»]
4XAMX-ray4.20C/E757-1446[»]
D/F1454-1744[»]
5JPMX-ray3.75A/D20-675[»]
B/E680-1446[»]
C/F1454-1744[»]
5JPNX-ray3.60A20-675[»]
B680-1446[»]
C1455-1744[»]
5JTWX-ray3.50A/D20-675[»]
B/E757-1446[»]
C/F1454-1744[»]
ProteinModelPortaliP0C0L4.
SMRiP0C0L4.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107181. 23 interactors.
107182. 2 interactors.
IntActiP0C0L4. 11 interactors.
STRINGi9606.ENSP00000396688.

Chemistry databases

DrugBankiDB00028. Intravenous Immunoglobulin.

PTM databases

iPTMnetiP0C0L4.
PhosphoSitePlusiP0C0L4.
UniCarbKBiP0C0L4.

Polymorphism and mutation databases

BioMutaiC4A.
DMDMi476007827.

Proteomic databases

EPDiP0C0L4.
MaxQBiP0C0L4.
PaxDbiP0C0L4.
PeptideAtlasiP0C0L4.
PRIDEiP0C0L4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000383325; ENSP00000372815; ENSG00000206340.
ENST00000421274; ENSP00000388662; ENSG00000227746.
ENST00000428956; ENSP00000396688; ENSG00000244731. [P0C0L4-1]
ENST00000498271; ENSP00000420212; ENSG00000244731. [P0C0L4-2]
GeneIDi720.
721.
KEGGihsa:720.
hsa:721.
UCSCiuc011doy.3. human. [P0C0L4-1]

Organism-specific databases

CTDi720.
721.
DisGeNETi100293534.
720.
721.
GeneCardsiC4A.
HGNCiHGNC:1323. C4A.
HPAiCAB009811.
CAB032603.
HPA046356.
HPA048287.
HPA050103.
MalaCardsiC4A.
MIMi120790. phenotype.
120810. gene.
152700. phenotype.
614374. phenotype.
614380. phenotype.
neXtProtiNX_P0C0L4.
OpenTargetsiENSG00000244731.
Orphaneti117. Behcet disease.
169147. Immunodeficiency due to an early component of complement deficiency.
536. Systemic lupus erythematosus.
PharmGKBiPA25903.
PA25904.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1366. Eukaryota.
ENOG410XRED. LUCA.
GeneTreeiENSGT00760000118982.
HOGENOMiHOG000290712.
HOVERGENiHBG107123.
InParanoidiP0C0L4.
KOiK03989.
OMAiDWFDIRS.
OrthoDBiEOG091G00FL.
PhylomeDBiP0C0L4.
TreeFamiTF313285.

Enzyme and pathway databases

ReactomeiR-HSA-166663. Initial triggering of complement.
R-HSA-174577. Activation of C3 and C5.
R-HSA-977606. Regulation of Complement cascade.
SABIO-RKP0C0L4.

Miscellaneous databases

EvolutionaryTraceiP0C0L4.
GeneWikiiC4A.
PMAP-CutDBB0QZR6.
PROiP0C0L4.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000206340.
GenevisibleiP0C0L4. HS.

Family and domain databases

Gene3Di1.20.91.20. 1 hit.
1.50.10.20. 1 hit.
2.60.40.690. 1 hit.
InterProiIPR009048. A-macroglobulin_rcpt-bd.
IPR011626. A2M_comp.
IPR002890. A2M_N.
IPR011625. A2M_N_2.
IPR000020. Anaphylatoxin/fibulin.
IPR018081. Anaphylatoxin_comp_syst.
IPR001840. Anaphylatoxn_comp_syst_dom.
IPR001599. Macroglobln_a2.
IPR019742. MacrogloblnA2_CS.
IPR019565. MacrogloblnA2_thiol-ester-bond.
IPR001134. Netrin_domain.
IPR018933. Netrin_module_non-TIMP.
IPR008930. Terpenoid_cyclase/PrenylTrfase.
IPR008993. TIMP-like_OB-fold.
[Graphical view]
PfamiPF00207. A2M. 1 hit.
PF07678. A2M_comp. 1 hit.
PF01835. A2M_N. 1 hit.
PF07703. A2M_N_2. 1 hit.
PF07677. A2M_recep. 1 hit.
PF01821. ANATO. 1 hit.
PF01759. NTR. 1 hit.
PF10569. Thiol-ester_cl. 1 hit.
[Graphical view]
PRINTSiPR00004. ANAPHYLATOXN.
SMARTiSM01360. A2M. 1 hit.
SM01359. A2M_N_2. 1 hit.
SM01361. A2M_recep. 1 hit.
SM00104. ANATO. 1 hit.
SM00643. C345C. 1 hit.
[Graphical view]
SUPFAMiSSF47686. SSF47686. 1 hit.
SSF48239. SSF48239. 1 hit.
SSF49410. SSF49410. 1 hit.
SSF50242. SSF50242. 1 hit.
PROSITEiPS00477. ALPHA_2_MACROGLOBULIN. 1 hit.
PS01177. ANAPHYLATOXIN_1. 1 hit.
PS01178. ANAPHYLATOXIN_2. 1 hit.
PS50189. NTR. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCO4A_HUMAN
AccessioniPrimary (citable) accession number: P0C0L4
Secondary accession number(s): A6H8M8
, A6NHJ5, A7E2V2, B0QZR6, B0V2C8, B2RUT6, B7ZVZ6, P01028, P78445, Q13160, Q13906, Q14033, Q14835, Q4LE82, Q5JNX2, Q5JQM8, Q6P4R1, Q6U2E5, Q6U2E8, Q6U2F0, Q6U2F3, Q6U2F4, Q6U2F6, Q6U2F8, Q6U2G0, Q96EG2, Q96SA8, Q9NPK5, Q9UIP5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: April 3, 2013
Last modified: November 30, 2016
This is version 127 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Blood group antigen proteins
    Nomenclature of blood group antigens and list of entries
  2. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.