P0C0L4 (CO4A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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:

1. Complement C4 beta chain
2. Complement C4-A alpha chain
3. C4a anaphylatoxin
4. C4b-A
5. C4d-A
6. Complement C4 gamma chain

Gene names

Name:	C4A
Synonyms:	CO4, CPAMD2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1744 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.19 Ref.21 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. Ref.19 Ref.21
Subunit structure	Circulates in blood as a disulfide-linked trimer of an alpha, beta and gamma chain.
Subcellular location	Secreted.
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. Ref.23
Post-translational modification	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. Ref.24 Ref.33
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. 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 (Ref.23). C4A6 allotype is deficient in hemolytic activity. Allotype C4A13 is infrequent.
Involvement in disease	Complement component 4A deficiency (C4AD) [MIM:614380]: A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 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. Note: 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. Ref.22 Ref.28
Sequence similarities	Contains 1 anaphylatoxin-like domain. Contains 1 NTR domain.
Sequence caution	The sequence AAB59537.1 differs from that shown. Reason: During cDNA synthesis, the 5' end has been inverted (Ref.6). The sequence BAE06071.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Complement pathway Immunity Inflammatory response Innate immunity
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Systemic lupus erythematosus
Domain	Signal
Molecular function	Blood group antigen
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Sulfation Thioester bond
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	complement activation Traceable author statement. Source: Reactome complement activation, classical pathway Inferred from electronic annotation. Source: UniProtKB-KW inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Traceable author statement. Source: Reactome negative regulation of endopeptidase activity Inferred from electronic annotation. Source: GOC regulation of complement activation Traceable author statement. Source: Reactome
Cellular_component	extracellular region Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: InterPro plasma membrane Traceable author statement. Source: Reactome
Molecular_function	endopeptidase inhibitor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P0C0L4-1)

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.

Isoform 2 (identifier: P0C0L4-2)

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

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

Chain

20 – 675

656

Complement C4 beta chain

PRO_0000005966

Propeptide

676 – 679

4

PRO_0000005967

Chain

680 – 1446

767

Complement C4-A alpha chain

PRO_0000005968

Chain

680 – 756

77

C4a anaphylatoxin

PRO_0000005969

Chain

757 – 1446

690

C4b-A

PRO_0000005970

Chain

957 – 1336

380

C4d-A

PRO_0000042698

Propeptide

1447 – 1453

7

PRO_0000005971

Chain

1454 – 1744

291

Complement C4 gamma chain

PRO_0000005972

Regions

Domain

702 – 736

35

Anaphylatoxin-like

Domain

1595 – 1742

148

NTR

Sites

Site

1125

1

Responsible for effective binding to form amide bonds with immune aggregates or protein antigens

Amino acid modifications

Modified residue

1417

1

Sulfotyrosine Ref.17

Modified residue

1420

1

Sulfotyrosine Ref.17

Modified residue

1422

1

Sulfotyrosine Ref.17

Glycosylation

226

1

N-linked (GlcNAc...) Ref.24 Ref.29 Ref.30

Glycosylation

862

1

N-linked (GlcNAc...) Ref.27

Glycosylation

1244

1

O-linked (GalNAc...) Ref.33

Glycosylation

1328

1

N-linked (GlcNAc...) Ref.27 Ref.29 Ref.30

Glycosylation

1391

1

N-linked (GlcNAc...) Ref.25 Ref.27 Ref.30

Disulfide bond

702 ↔ 728

By similarity

Disulfide bond

703 ↔ 735

By similarity

Disulfide bond

716 ↔ 736

By similarity

Disulfide bond

1595 ↔ 1673

By similarity

Disulfide bond

1618 ↔ 1742

By similarity

Cross-link

1010 ↔ 1013

Isoglutamyl cysteine thioester (Cys-Gln)

Natural variations

Alternative sequence

1458 – 1503

46

Missing in isoform 2.

VSP_046252

Natural variant

141

1

L → V.
Corresponds to variant rs9296005 [ dbSNP | Ensembl ].

VAR_069154

Natural variant

347

1

S → Y in allotype C4A3a, allotype C4A6. Ref.2 Ref.4 Ref.5
Corresponds to variant rs150969927 [ dbSNP | Ensembl ].

VAR_019778

Natural variant

418

1

V → A in allotype C4A4. Ref.1

VAR_069155

Natural variant

477

1

R → W in allotype C4A6. Ref.8

VAR_001987

Natural variant

549

1

H → P. Ref.8
Corresponds to variant rs2229405 [ dbSNP | Ensembl ].

VAR_069156

Natural variant

564

1

A → D.
Corresponds to variant rs35277227 [ dbSNP | Ensembl ].

VAR_069157

Natural variant

726

1

P → L in allotype C4A3a. Ref.2

VAR_001988

Natural variant

727

1

D → N. Ref.7

VAR_019779

Natural variant

907

1

A → T. Ref.8
Corresponds to variant rs141302872 [ dbSNP | Ensembl ].

VAR_019780

Natural variant

1073

1

D → G in allotype C4A1, allotype C4A2. Ref.5 Ref.8 Ref.12
Corresponds to variant rs147162052 [ dbSNP | Ensembl ].

VAR_069158

Natural variant

1176

1

N → S in allotype C4A1. Ref.3 Ref.4 Ref.8 Ref.12
Corresponds to variant rs17874654 [ dbSNP | Ensembl ].

VAR_069159

Natural variant

1201

1

T → S in allotype C4A4. Ref.1

VAR_001992

Natural variant

1207

1

V → A in allotype C4A1, allotype C4A13. Ref.8 Ref.12 Ref.16
Corresponds to variant rs28357075 [ dbSNP | Ensembl ].

VAR_001993

Natural variant

1210

1

L → R in allotype C4A1, allotype C4A13. Ref.8 Ref.12 Ref.16
Corresponds to variant rs28357076 [ dbSNP | Ensembl ].

VAR_001994

Natural variant

1286

1

S → A in allotype C4A1, allotype C4A3a, allotype C4A6. Ref.2 Ref.3 Ref.4 Ref.5 Ref.12 Ref.16 Ref.35
Corresponds to variant rs201016130 [ dbSNP | Ensembl ].

VAR_001995

Experimental info

Sequence conflict

217

1

A → V in AAI71786. Ref.5

Sequence conflict

643

1

A → S in AAH63289. Ref.5

Sequence conflict

729

1

R → W in AAH63289. Ref.5

Sequence conflict

1013

1

Q → E AA sequence Ref.11

Sequence conflict

1013

1

Q → E AA sequence Ref.12

Sequence conflict

1013

1

Q → E AA sequence Ref.13

Sequence conflict

1109 – 1110

2

SQ → IA AA sequence Ref.12

Sequence conflict

1182

1

K → I in AAH63289. Ref.5

Sequence conflict

1245

1

P → Q in AAH63289. Ref.5

Sequence conflict

1271

1

H → V AA sequence Ref.12

Sequence conflict

1271

1

H → V AA sequence Ref.16

Sequence conflict

1300

1

R → V AA sequence Ref.12

Sequence conflict

1300

1

R → V AA sequence Ref.16

Sequence conflict

1419 – 1421

3

Missing in AAB59537. Ref.1

Sequence conflict

1635

1

D → G in AAH12372. Ref.5

Sequence conflict

1637

1

R → S in AAI44547. Ref.5

Sequence conflict

1637

1

R → S in AAI46850. Ref.5

Sequence conflict

1678

1

E → G in AAI71786. Ref.5

Sequence conflict

1704

1

D → E in AAH12372. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1744

Helix Strand Turn

Details...

Helix

997 – 1001

5

Helix

1011 – 1030

20

Helix

1041 – 1057

17

Helix

1076 – 1089

14

Helix

1090 – 1092

3

Helix

1097 – 1107

11

Helix

1108 – 1110

3

Helix

1126 – 1132

7

Helix

1137 – 1153

17

Turn

1158 – 1161

4

Helix

1162 – 1185

24

Helix

1190 – 1202

13

Helix

1207 – 1218

12

Helix

1259 – 1275

17

Helix

1280 – 1292

13

Helix

1302 – 1319

18

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified April 3, 2013. Version 2. Checksum: 9396A4CC4DA3602C	FASTA	1,744	192,785
	10 20 30 40 50 60 MRLLWGLIWA SSFFTLSLQK PRLLLFSPSV VHLGVPLSVG VQLQDVPRGQ VVKGSVFLRN 70 80 90 100 110 120 PSRNNVPCSP KVDFTLSSER DFALLSLQVP LKDAKSCGLH QLLRGPEVQL VAHSPWLKDS 130 140 150 160 170 180 LSRTTNIQGI NLLFSSRRGH LFLQTDQPIY NPGQRVRYRV FALDQKMRPS TDTITVMVEN 190 200 210 220 230 240 SHGLRVRKKE VYMPSSIFQD DFVIPDISEP GTWKISARFS DGLESNSSTQ FEVKKYVLPN 250 260 270 280 290 300 FEVKITPGKP YILTVPGHLD EMQLDIQARY IYGKPVQGVA YVRFGLLDED GKKTFFRGLE 310 320 330 340 350 360 SQTKLVNGQS HISLSKAEFQ DALEKLNMGI TDLQGLRLYV AAAIIESPGG EMEEAELTSW 370 380 390 400 410 420 YFVSSPFSLD LSKTKRHLVP GAPFLLQALV REMSGSPASG IPVKVSATVS SPGSVPEVQD 430 440 450 460 470 480 IQQNTDGSGQ VSIPIIIPQT ISELQLSVSA GSPHPAIARL TVAAPPSGGP GFLSIERPDS 490 500 510 520 530 540 RPPRVGDTLN LNLRAVGSGA TFSHYYYMIL SRGQIVFMNR EPKRTLTSVS VFVDHHLAPS 550 560 570 580 590 600 FYFVAFYYHG DHPVANSLRV DVQAGACEGK LELSVDGAKQ YRNGESVKLH LETDSLALVA 610 620 630 640 650 660 LGALDTALYA AGSKSHKPLN MGKVFEAMNS YDLGCGPGGG DSALQVFQAA GLAFSDGDQW 670 680 690 700 710 720 TLSRKRLSCP KEKTTRKKRN VNFQKAINEK LGQYASPTAK RCCQDGVTRL PMMRSCEQRA 730 740 750 760 770 780 ARVQQPDCRE PFLSCCQFAE SLRKKSRDKG QAGLQRALEI LQEEDLIDED DIPVRSFFPE 790 800 810 820 830 840 NWLWRVETVD RFQILTLWLP DSLTTWEIHG LSLSKTKGLC VATPVQLRVF REFHLHLRLP 850 860 870 880 890 900 MSVRRFEQLE LRPVLYNYLD KNLTVSVHVS PVEGLCLAGG GGLAQQVLVP AGSARPVAFS 910 920 930 940 950 960 VVPTAAAAVS LKVVARGSFE FPVGDAVSKV LQIEKEGAIH REELVYELNP LDHRGRTLEI 970 980 990 1000 1010 1020 PGNSDPNMIP DGDFNSYVRV TASDPLDTLG SEGALSPGGV ASLLRLPRGC GEQTMIYLAP 1030 1040 1050 1060 1070 1080 TLAASRYLDK TEQWSTLPPE TKDHAVDLIQ KGYMRIQQFR KADGSYAAWL SRDSSTWLTA 1090 1100 1110 1120 1130 1140 FVLKVLSLAQ EQVGGSPEKL QETSNWLLSQ QQADGSFQDP CPVLDRSMQG GLVGNDETVA 1150 1160 1170 1180 1190 1200 LTAFVTIALH HGLAVFQDEG AEPLKQRVEA SISKANSFLG EKASAGLLGA HAAAITAYAL 1210 1220 1230 1240 1250 1260 TLTKAPVDLL GVAHNNLMAM AQETGDNLYW GSVTGSQSNA VSPTPAPRNP SDPMPQAPAL 1270 1280 1290 1300 1310 1320 WIETTAYALL HLLLHEGKAE MADQASAWLT RQGSFQGGFR STQDTVIALD ALSAYWIASH 1330 1340 1350 1360 1370 1380 TTEERGLNVT LSSTGRNGFK SHALQLNNRQ IRGLEEELQF SLGSKINVKV GGNSKGTLKV 1390 1400 1410 1420 1430 1440 LRTYNVLDMK NTTCQDLQIE VTVKGHVEYT MEANEDYEDY EYDELPAKDD PDAPLQPVTP 1450 1460 1470 1480 1490 1500 LQLFEGRRNR RRREAPKVVE EQESRVHYTV CIWRNGKVGL SGMAIADVTL LSGFHALRAD 1510 1520 1530 1540 1550 1560 LEKLTSLSDR YVSHFETEGP HVLLYFDSVP TSRECVGFEA VQEVPVGLVQ PASATLYDYY 1570 1580 1590 1600 1610 1620 NPERRCSVFY GAPSKSRLLA TLCSAEVCQC AEGKCPRQRR ALERGLQDED GYRMKFACYY 1630 1640 1650 1660 1670 1680 PRVEYGFQVK VLREDSRAAF RLFETKITQV LHFTKDVKAA ANQMRNFLVR ASCRLRLEPG 1690 1700 1710 1720 1730 1740 KEYLIMGLDG ATYDLEGHPQ YLLDSNSWIE EMPSERLCRS TRQRAACAQL NDFLQEYGTQ GCQV
	Isoform 2 [UniParc]. Checksum: 6169C0C84E28C512	FASTA	1,698	187,704
	10 20 30 40 50 60 MRLLWGLIWA SSFFTLSLQK PRLLLFSPSV VHLGVPLSVG VQLQDVPRGQ VVKGSVFLRN 70 80 90 100 110 120 PSRNNVPCSP KVDFTLSSER DFALLSLQVP LKDAKSCGLH QLLRGPEVQL VAHSPWLKDS 130 140 150 160 170 180 LSRTTNIQGI NLLFSSRRGH LFLQTDQPIY NPGQRVRYRV FALDQKMRPS TDTITVMVEN 190 200 210 220 230 240 SHGLRVRKKE VYMPSSIFQD DFVIPDISEP GTWKISARFS DGLESNSSTQ FEVKKYVLPN 250 260 270 280 290 300 FEVKITPGKP YILTVPGHLD EMQLDIQARY IYGKPVQGVA YVRFGLLDED GKKTFFRGLE 310 320 330 340 350 360 SQTKLVNGQS HISLSKAEFQ DALEKLNMGI TDLQGLRLYV AAAIIESPGG EMEEAELTSW 370 380 390 400 410 420 YFVSSPFSLD LSKTKRHLVP GAPFLLQALV REMSGSPASG IPVKVSATVS SPGSVPEVQD 430 440 450 460 470 480 IQQNTDGSGQ VSIPIIIPQT ISELQLSVSA GSPHPAIARL TVAAPPSGGP GFLSIERPDS 490 500 510 520 530 540 RPPRVGDTLN LNLRAVGSGA TFSHYYYMIL SRGQIVFMNR EPKRTLTSVS VFVDHHLAPS 550 560 570 580 590 600 FYFVAFYYHG DHPVANSLRV DVQAGACEGK LELSVDGAKQ YRNGESVKLH LETDSLALVA 610 620 630 640 650 660 LGALDTALYA AGSKSHKPLN MGKVFEAMNS YDLGCGPGGG DSALQVFQAA GLAFSDGDQW 670 680 690 700 710 720 TLSRKRLSCP KEKTTRKKRN VNFQKAINEK LGQYASPTAK RCCQDGVTRL PMMRSCEQRA 730 740 750 760 770 780 ARVQQPDCRE PFLSCCQFAE SLRKKSRDKG QAGLQRALEI LQEEDLIDED DIPVRSFFPE 790 800 810 820 830 840 NWLWRVETVD RFQILTLWLP DSLTTWEIHG LSLSKTKGLC VATPVQLRVF REFHLHLRLP 850 860 870 880 890 900 MSVRRFEQLE LRPVLYNYLD KNLTVSVHVS PVEGLCLAGG GGLAQQVLVP AGSARPVAFS 910 920 930 940 950 960 VVPTAAAAVS LKVVARGSFE FPVGDAVSKV LQIEKEGAIH REELVYELNP LDHRGRTLEI 970 980 990 1000 1010 1020 PGNSDPNMIP DGDFNSYVRV TASDPLDTLG SEGALSPGGV ASLLRLPRGC GEQTMIYLAP 1030 1040 1050 1060 1070 1080 TLAASRYLDK TEQWSTLPPE TKDHAVDLIQ KGYMRIQQFR KADGSYAAWL SRDSSTWLTA 1090 1100 1110 1120 1130 1140 FVLKVLSLAQ EQVGGSPEKL QETSNWLLSQ QQADGSFQDP CPVLDRSMQG GLVGNDETVA 1150 1160 1170 1180 1190 1200 LTAFVTIALH HGLAVFQDEG AEPLKQRVEA SISKANSFLG EKASAGLLGA HAAAITAYAL 1210 1220 1230 1240 1250 1260 TLTKAPVDLL GVAHNNLMAM AQETGDNLYW GSVTGSQSNA VSPTPAPRNP SDPMPQAPAL 1270 1280 1290 1300 1310 1320 WIETTAYALL HLLLHEGKAE MADQASAWLT RQGSFQGGFR STQDTVIALD ALSAYWIASH 1330 1340 1350 1360 1370 1380 TTEERGLNVT LSSTGRNGFK SHALQLNNRQ IRGLEEELQF SLGSKINVKV GGNSKGTLKV 1390 1400 1410 1420 1430 1440 LRTYNVLDMK NTTCQDLQIE VTVKGHVEYT MEANEDYEDY EYDELPAKDD PDAPLQPVTP 1450 1460 1470 1480 1490 1500 LQLFEGRRNR RRREAPKLTS LSDRYVSHFE TEGPHVLLYF DSVPTSRECV GFEAVQEVPV 1510 1520 1530 1540 1550 1560 GLVQPASATL YDYYNPERRC SVFYGAPSKS RLLATLCSAE VCQCAEGKCP RQRRALERGL 1570 1580 1590 1600 1610 1620 QDEDGYRMKF ACYYPRVEYG FQVKVLREDS RAAFRLFETK ITQVLHFTKD VKAAANQMRN 1630 1640 1650 1660 1670 1680 FLVRASCRLR LEPGKEYLIM GLDGATYDLE GHPQYLLDSN SWIEEMPSER LCRSTRQRAA 1690 CAQLNDFLQE YGTQGCQV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The structural basis of the multiple forms of human complement component C4." Belt K.T., Carroll M.C., Porter R.R. Cell 36:907-914(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS ALA-418 AND SER-1201. Tissue: Liver.
[2]	"The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene." Yu C.Y. J. Immunol. 146:1057-1066(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS TYR-347; LEU-726 AND ALA-1286.
[3]	"Preparation of a set of expression-ready clones of mammalian long cDNAs encoding large proteins by the ORF trap cloning method." Nakajima D., Saito K., Yamakawa H., Kikuno R.F., Nakayama M., Ohara R., Okazaki N., Koga H., Nagase T., Ohara O. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANTS SER-1176 AND ALA-1286. Tissue: Brain.
[4]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANTS TYR-347; SER-1176 AND ALA-1286.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANTS TYR-347; GLY-1073 AND ALA-1286. Tissue: Brain.
[6]	"Polymorphism of human complement component C4." Belt K.T., Yu C.Y., Carroll M.C., Porter R.R. Immunogenetics 21:173-180(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22 AND 1056-1225.
[7]	"Characterisation of the novel gene G11 lying adjacent to the complement C4A gene in the human major histocompatibility complex." Sargent C.A., Anderson M.J., Hsieh S.-L., Kendall E., Gomez-Escobar N., Campbell R.D. Hum. Mol. Genet. 3:481-488(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-21, VARIANT ASN-727.
[8]	"Molecular genetics of complement C4: implications for MHC evolution and disease susceptibility gene mapping." Sayer D., Puschendorf M., Wetherall J. Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 448-570 AND 692-1225, VARIANTS TRP-477; PRO-549; THR-907; GLY-1073; SER-1176; ALA-1207 AND ARG-1210.
[9]	"Complete primary structure of human C4a anaphylatoxin." Moon K.E., Gorski J.P., Hugli T.E. J. Biol. Chem. 256:8685-8692(1981) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 680-756.
[10]	"Importance of the alpha 3-fragment of complement C4 for the binding with C4b-binding protein." Hessing M., van 't Veer C., Hackeng T.M., Bouma B.N., Iwanaga S. FEBS Lett. 271:131-136(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 757-771 AND 980-990.
[11]	"Amino acid sequence around the thiol and reactive acyl groups of human complement component C4." Campbell R.D., Gagnon J., Porter R.R. Biochem. J. 199:359-370(1981) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 957-1044.
[12]	"The chemical structure of the C4d fragment of the human complement component C4." Chakravarti D.N., Campbell R.D., Porter R.R. Mol. Immunol. 24:1187-1197(1987) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 957-1336, VARIANTS GLY-1073; SER-1176; ALA-1207; ARG-1210 AND ALA-1286.
[13]	"Sequence determination of the thiolester site of the fourth component of human complement." Harrison R.A., Thomas M.L., Tack B.F. Proc. Natl. Acad. Sci. U.S.A. 78:7388-7392(1981) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 990-1037.
[14]	"C4d DNA sequences of two infrequent human allotypes (C4A13 and C4B12) and the presence of signal sequences enhancing recombination." Martinez-Quiles N., Paz-Artal E., Moreno-Pelayo M.A., Longas J., Ferre-Lopez S., Rosal M., Arnaiz-Villena A. J. Immunol. 161:3438-3443(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1055-1225 (ALLOTYPE C4A13).
[15]	"Cloning of a human complement component C4 gene." Carroll M.C., Porter R.R. Proc. Natl. Acad. Sci. U.S.A. 80:264-267(1983) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1195-1294.
[16]	"Amino acid sequence of a polymorphic segment from fragment C4d of human complement component C4." Chakravarti D.N., Campbell R.D., Gagnon J. FEBS Lett. 154:387-390(1983) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 1199-1304, VARIANTS ALA-1207; ARG-1210 AND ALA-1286.
[17]	"Identification of the site of sulfation of the fourth component of human complement." Hortin G., Sims H., Strauss A.W. J. Biol. Chem. 261:1786-1793(1986) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 1405-1431, SULFATION AT TYR-1417; TYR-1420 AND TYR-1422.
[18]	"Use of a cDNA clone for the fourth component of human complement (C4) for analysis of a genetic deficiency of C4 in guinea pig." Whitehead A.S., Goldberger G., Woods D.E., Markham A.F., Colten H.R. Proc. Natl. Acad. Sci. U.S.A. 80:5387-5391(1983) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1448-1474.
[19]	"Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A." Carroll M.C., Fathallah D.M., Bergamaschini L., Alicot E.M., Isenman D.E. Proc. Natl. Acad. Sci. U.S.A. 87:6868-6872(1990) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INVOLVEMENT OF ASP-1125 IN IMMUNOGLOBULIN-BINDING AND HEMOLYSIS.
[20]	"Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to nonexpression." Barba G., Rittner C., Schneider P.M. J. Clin. Invest. 91:1681-1686(1993) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN C4AD.
[21]	"The reaction mechanism of the internal thioester in the human complement component C4." Dodds A.W., Ren X.D., Willis A.C., Law S.K. Nature 379:177-179(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[22]	"Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes." Lokki M.L., Circolo A., Ahokas P., Rupert K.L., Yu C.Y., Colten H.R. J. Immunol. 162:3687-3693(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN SLE.
[23]	"Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4." Blanchong C.A., Chung E.K., Rupert K.L., Yang Y., Yang Z., Zhou B., Moulds J.M., Yu C.Y. Int. Immunopharmacol. 1:365-392(2001) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW, DESCRIPTION OF ALLOTYPES, TISSUE SPECIFICITY.
[24]	"Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry." Zhang H., Li X.-J., Martin D.B., Aebersold R. Nat. Biotechnol. 21:660-666(2003) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT ASN-226.
[25]	"Screening for N-glycosylated proteins by liquid chromatography mass spectrometry." Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R. Proteomics 4:454-465(2004) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1391, MASS SPECTROMETRY. Tissue: Plasma.
[26]	"Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity." Yu C.Y., Belt K.T., Giles C.M., Campbell R.D., Porter R.R. EMBO J. 5:2873-2881(1986) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURAL BASIS OF POLYMORPHISM.
[27]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-862; ASN-1328 AND ASN-1391, MASS SPECTROMETRY. Tissue: Plasma.
[28]	"Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans." Yang Y., Chung E.K., Wu Y.L., Savelli S.L., Nagaraja H.N., Zhou B., Hebert M., Jones K.N., Shu Y., Kitzmiller K., Blanchong C.A., McBride K.L., Higgins G.C., Rennebohm R.M., Rice R.R., Hackshaw K.V., Roubey R.A., Grossman J.M. , Tsao B.P., Birmingham D.J., Rovin B.H., Hebert L.A., Yu C.Y. Am. J. Hum. Genet. 80:1037-1054(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN SLE.
[29]	"Identification of N-linked glycoproteins in human milk by hydrophilic interaction liquid chromatography and mass spectrometry." Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F. Proteomics 8:3833-3847(2008) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-226 AND ASN-1328, MASS SPECTROMETRY. Tissue: Milk.
[30]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-226; ASN-1328 AND ASN-1391, MASS SPECTROMETRY. Tissue: Liver.
[31]	"Enrichment of glycopeptides for glycan structure and attachment site identification." Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., Larson G. Nat. Methods 6:809-811(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS], STRUCTURE OF CARBOHYDRATES, MASS SPECTROMETRY. Tissue: Cerebrospinal fluid.
[32]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[33]	"LC-MS/MS characterization of O-glycosylation sites and glycan structures of human cerebrospinal fluid glycoproteins." Halim A., Ruetschi U., Larson G., Nilsson J. J. Proteome Res. 12:573-584(2013) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT THR-1244, MASS SPECTROMETRY.
[34]	"X-ray crystal structure of the C4d fragment of human complement component C4." van den Elsen J.M., Martin A., Wong V., Clemenza L., Rose D.R., Isenman D.E. J. Mol. Biol. 322:1103-1115(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 957-1323.
[35]	"The coding sequence of the hemolytically inactive C4A6 allotype of human complement component C4 reveals that a single arginine to tryptophan substitution at beta-chain residue 458 is the likely cause of the defect." Anderson M.J., Milner C.M., Cotton G.H., Campbell R.D. J. Immunol. 148:2795-2802(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ALA-1286 (ALLOTYPE C4A6).
+	Additional computationally mapped references.

Web resources

dbRBC/BGMUT

Blood group antigen gene mutation database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00032258.

PIR

B20807.
C4HU. I56095.

RefSeq

NP_001002029.3. NM_001002029.3.
NP_001239133.1. NM_001252204.1.
NP_009224.2. NM_007293.2.

UniGene

Hs.534847.
Hs.720022.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HZF	X-ray	2.30	A	957-1323	[»]
4FXG	X-ray	3.75	A/D	20-675	[»]
			B/E	680-1446	[»]
			C/F	1454-1744	[»]
4FXK	X-ray	3.60	A	20-675	[»]
			B	680-1446	[»]
			C	1454-1744	[»]

ProteinModelPortal

P0C0L4.

ModBase

Search...

Protein-protein interaction databases

IntAct

P0C0L4. 9 interactions.

PTM databases

PhosphoSite

P0C0L4.

Polymorphism databases

DMDM

81175238.

Proteomic databases

PaxDb

P0C0L4.

PRIDE

P0C0L4.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000383325; ENSP00000372815; ENSG00000206340.
ENST00000421274; ENSP00000388662; ENSG00000227746.
ENST00000428956; ENSP00000396688; ENSG00000244731.
ENST00000498271; ENSP00000420212; ENSG00000244731.

GeneID

720.
721.

KEGG

hsa:720.
hsa:721.

Organism-specific databases

CTD

720.
721.

GeneCards

GC06P031954.

HGNC

HGNC:1323. C4A.

HPA

CAB009811.
CAB032603.

MIM

120790. phenotype.
120810. gene.
152700. phenotype.
614374. phenotype.
614380. phenotype.

neXtProt

NX_P0C0L4.

Orphanet

169147. Immunodeficiency due to an early component of complement deficiency.

PharmGKB

PA25903.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG2373.

HOVERGEN

HBG107123.

InParanoid

P0C0L4.

KO

K03989.

OrthoDB

EOG4JM7NW.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P0C0L4.

Bgee

P0C0L4.

Genevestigator

P0C0L4.

GermOnline

ENSG00000204319. Homo sapiens.

Family and domain databases

Gene3D

1.20.91.20. 1 hit.
2.60.40.690. 1 hit.

InterPro

IPR009048. A-macroglobulin_rcpt-bd.
IPR011626. A2M_comp.
IPR002890. A2M_N.
IPR011625. A2M_N_2.
IPR000020. Anaphylatoxin/fibulin.
IPR018081. Anaphylatoxin_.
IPR001840. Anaphylatoxn.
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]

Pfam

PF00207. 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]

PRINTS

PR00004. ANAPHYLATOXN.

SMART

SM00104. ANATO. 1 hit.
SM00643. C345C. 1 hit.
[Graphical view]

SUPFAM

SSF49410. AM_receptor_bind. 1 hit.
SSF47686. Anaphylatoxin. 1 hit.
SSF48239. Terp_cyc_toroid. 1 hit.
SSF50242. TIMP_like. 1 hit.

PROSITE

PS00477. ALPHA_2_MACROGLOBULIN. 1 hit.
PS01177. ANAPHYLATOXIN_1. 1 hit.
PS01178. ANAPHYLATOXIN_2. 1 hit.
PS50189. NTR. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P0C0L4.

GenomeRNAi

720.

NextBio

13630656.

PMAP-CutDB

B0QZR6.

SOURCE

Search...

Entry information

Entry name

CO4A_HUMAN

Accession

Primary (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 history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	April 3, 2013
Last modified:	May 1, 2013
This is version 90 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.