CO4A_HUMAN
ID CO4A_HUMAN Reviewed; 1744 AA.
AC P0C0L4; A6H8M8; A6NHJ5; A7E2V2; B0QZR6; B0V2C8; B2RUT6; B7ZVZ6; P01028;
AC P78445; Q13160; Q13906; Q14033; Q14835; Q4LE82; Q5JNX2; Q5JQM8; Q6P4R1;
AC Q6U2E5; Q6U2E8; Q6U2F0; Q6U2F3; Q6U2F4; Q6U2F6; Q6U2F8; Q6U2G0; Q96EG2;
AC Q96SA8; Q9NPK5; Q9UIP5;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 2.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Complement C4-A;
DE AltName: Full=Acidic complement C4;
DE AltName: Full=C3 and PZP-like alpha-2-macroglobulin domain-containing protein 2;
DE Contains:
DE RecName: Full=Complement C4 beta chain;
DE Contains:
DE RecName: Full=Complement C4-A alpha chain;
DE Contains:
DE RecName: Full=C4a anaphylatoxin;
DE Contains:
DE RecName: Full=C4b-A;
DE Contains:
DE RecName: Full=C4d-A;
DE Contains:
DE RecName: Full=Complement C4 gamma chain;
DE Flags: Precursor;
GN Name=C4A; Synonyms=CO4, CPAMD2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ALA-418 AND SER-1201.
RC TISSUE=Liver;
RX PubMed=6546707; DOI=10.1016/0092-8674(84)90040-0;
RA Belt K.T., Carroll M.C., Porter R.R.;
RT "The structural basis of the multiple forms of human complement component
RT C4.";
RL Cell 36:907-914(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS TYR-347; LEU-726 AND
RP ALA-1286.
RX PubMed=1988494;
RA Yu C.Y.;
RT "The complete exon-intron structure of a human complement component C4A
RT gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase
RT gene.";
RL J. Immunol. 146:1057-1066(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS SER-1176
RP AND ALA-1286.
RC TISSUE=Brain;
RA Nakajima D., Saito K., Yamakawa H., Kikuno R.F., Nakayama M., Ohara R.,
RA Okazaki N., Koga H., Nagase T., Ohara O.;
RT "Preparation of a set of expression-ready clones of mammalian long cDNAs
RT encoding large proteins by the ORF trap cloning method.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS TYR-347;
RP SER-1176 AND ALA-1286.
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP TYR-347; GLY-1073 AND ALA-1286.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22 AND 1056-1225.
RX PubMed=3838531; DOI=10.1007/bf00364869;
RA Belt K.T., Yu C.Y., Carroll M.C., Porter R.R.;
RT "Polymorphism of human complement component C4.";
RL Immunogenetics 21:173-180(1985).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-21, AND VARIANT ASN-727.
RX PubMed=8012361; DOI=10.1093/hmg/3.3.481;
RA Sargent C.A., Anderson M.J., Hsieh S.-L., Kendall E., Gomez-Escobar N.,
RA Campbell R.D.;
RT "Characterisation of the novel gene G11 lying adjacent to the complement
RT C4A gene in the human major histocompatibility complex.";
RL Hum. Mol. Genet. 3:481-488(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 448-570 AND 692-1225, AND VARIANTS
RP TRP-477; PRO-549; THR-907; GLY-1073; SER-1176; ALA-1207 AND ARG-1210.
RA Sayer D., Puschendorf M., Wetherall J.;
RT "Molecular genetics of complement C4: implications for MHC evolution and
RT disease susceptibility gene mapping.";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP PROTEIN SEQUENCE OF 680-756.
RX PubMed=6167582; DOI=10.1016/s0021-9258(19)68898-8;
RA Moon K.E., Gorski J.P., Hugli T.E.;
RT "Complete primary structure of human C4a anaphylatoxin.";
RL J. Biol. Chem. 256:8685-8692(1981).
RN [10]
RP PROTEIN SEQUENCE OF 757-771 AND 980-990.
RX PubMed=1699796; DOI=10.1016/0014-5793(90)80389-z;
RA Hessing M., van 't Veer C., Hackeng T.M., Bouma B.N., Iwanaga S.;
RT "Importance of the alpha 3-fragment of complement C4 for the binding with
RT C4b-binding protein.";
RL FEBS Lett. 271:131-136(1990).
RN [11]
RP PROTEIN SEQUENCE OF 957-1044.
RX PubMed=6978711; DOI=10.1042/bj1990359;
RA Campbell R.D., Gagnon J., Porter R.R.;
RT "Amino acid sequence around the thiol and reactive acyl groups of human
RT complement component C4.";
RL Biochem. J. 199:359-370(1981).
RN [12]
RP PROTEIN SEQUENCE OF 957-1336, AND VARIANTS GLY-1073; SER-1176; ALA-1207;
RP ARG-1210 AND ALA-1286.
RX PubMed=3696167; DOI=10.1016/0161-5890(87)90165-9;
RA Chakravarti D.N., Campbell R.D., Porter R.R.;
RT "The chemical structure of the C4d fragment of the human complement
RT component C4.";
RL Mol. Immunol. 24:1187-1197(1987).
RN [13]
RP PROTEIN SEQUENCE OF 990-1037.
RX PubMed=6950384; DOI=10.1073/pnas.78.12.7388;
RA Harrison R.A., Thomas M.L., Tack B.F.;
RT "Sequence determination of the thiolester site of the fourth component of
RT human complement.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:7388-7392(1981).
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1055-1225 (ALLOTYPE C4A13).
RX PubMed=9759862;
RA Martinez-Quiles N., Paz-Artal E., Moreno-Pelayo M.A., Longas J.,
RA Ferre-Lopez S., Rosal M., Arnaiz-Villena A.;
RT "C4d DNA sequences of two infrequent human allotypes (C4A13 and C4B12) and
RT the presence of signal sequences enhancing recombination.";
RL J. Immunol. 161:3438-3443(1998).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1195-1294.
RX PubMed=6572000; DOI=10.1073/pnas.80.1.264;
RA Carroll M.C., Porter R.R.;
RT "Cloning of a human complement component C4 gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:264-267(1983).
RN [16]
RP PROTEIN SEQUENCE OF 1199-1304, AND VARIANTS ALA-1207; ARG-1210 AND
RP ALA-1286.
RX PubMed=6832377; DOI=10.1016/0014-5793(83)80188-4;
RA Chakravarti D.N., Campbell R.D., Gagnon J.;
RT "Amino acid sequence of a polymorphic segment from fragment C4d of human
RT complement component C4.";
RL FEBS Lett. 154:387-390(1983).
RN [17]
RP PROTEIN SEQUENCE OF 1405-1431, AND SULFATION AT TYR-1417; TYR-1420 AND
RP TYR-1422.
RX PubMed=3944109; DOI=10.1016/s0021-9258(17)36009-x;
RA Hortin G., Sims H., Strauss A.W.;
RT "Identification of the site of sulfation of the fourth component of human
RT complement.";
RL J. Biol. Chem. 261:1786-1793(1986).
RN [18]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1448-1474.
RX PubMed=6577433; DOI=10.1073/pnas.80.17.5387;
RA Whitehead A.S., Goldberger G., Woods D.E., Markham A.F., Colten H.R.;
RT "Use of a cDNA clone for the fourth component of human complement (C4) for
RT analysis of a genetic deficiency of C4 in guinea pig.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:5387-5391(1983).
RN [19]
RP FUNCTION, AND INVOLVEMENT OF ASP-1125 IN IMMUNOGLOBULIN-BINDING AND
RP HEMOLYSIS.
RX PubMed=2395880; DOI=10.1073/pnas.87.17.6868;
RA Carroll M.C., Fathallah D.M., Bergamaschini L., Alicot E.M., Isenman D.E.;
RT "Substitution of a single amino acid (aspartic acid for histidine) converts
RT the functional activity of human complement C4B to C4A.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6868-6872(1990).
RN [20]
RP INVOLVEMENT IN C4AD.
RX PubMed=8473511; DOI=10.1172/jci116377;
RA Barba G., Rittner C., Schneider P.M.;
RT "Genetic basis of human complement C4A deficiency. Detection of a point
RT mutation leading to nonexpression.";
RL J. Clin. Invest. 91:1681-1686(1993).
RN [21]
RP FUNCTION.
RX PubMed=8538770; DOI=10.1038/379177a0;
RA Dodds A.W., Ren X.D., Willis A.C., Law S.K.;
RT "The reaction mechanism of the internal thioester in the human complement
RT component C4.";
RL Nature 379:177-179(1996).
RN [22]
RP INVOLVEMENT IN SLE.
RX PubMed=10092831;
RA Lokki M.L., Circolo A., Ahokas P., Rupert K.L., Yu C.Y., Colten H.R.;
RT "Deficiency of human complement protein C4 due to identical frameshift
RT mutations in the C4A and C4B genes.";
RL J. Immunol. 162:3687-3693(1999).
RN [23]
RP REVIEW, DESCRIPTION OF ALLOTYPES, AND TISSUE SPECIFICITY.
RX PubMed=11367523; DOI=10.1016/s1567-5769(01)00019-4;
RA Blanchong C.A., Chung E.K., Rupert K.L., Yang Y., Yang Z., Zhou B.,
RA Moulds J.M., Yu C.Y.;
RT "Genetic, structural and functional diversities of human complement
RT components C4A and C4B and their mouse homologues, Slp and C4.";
RL Int. Immunopharmacol. 1:365-392(2001).
RN [24]
RP GLYCOSYLATION AT ASN-226.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [25]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1391.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [26]
RP STRUCTURAL BASIS OF POLYMORPHISM.
RX PubMed=2431902; DOI=10.1002/j.1460-2075.1986.tb04582.x;
RA Yu C.Y., Belt K.T., Giles C.M., Campbell R.D., Porter R.R.;
RT "Structural basis of the polymorphism of human complement components C4A
RT and C4B: gene size, reactivity and antigenicity.";
RL EMBO J. 5:2873-2881(1986).
RN [27]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-862; ASN-1328 AND ASN-1391.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [28]
RP INVOLVEMENT IN SLE.
RX PubMed=17503323; DOI=10.1086/518257;
RA Yang Y., Chung E.K., Wu Y.L., Savelli S.L., Nagaraja H.N., Zhou B.,
RA Hebert M., Jones K.N., Shu Y., Kitzmiller K., Blanchong C.A., McBride K.L.,
RA Higgins G.C., Rennebohm R.M., Rice R.R., Hackshaw K.V., Roubey R.A.,
RA Grossman J.M., Tsao B.P., Birmingham D.J., Rovin B.H., Hebert L.A.,
RA Yu C.Y.;
RT "Gene copy-number variation and associated polymorphisms of complement
RT component C4 in human systemic lupus erythematosus (SLE): low copy number
RT is a risk factor for and high copy number is a protective factor against
RT SLE susceptibility in European Americans.";
RL Am. J. Hum. Genet. 80:1037-1054(2007).
RN [29]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-226 AND ASN-1328.
RC TISSUE=Milk;
RX PubMed=18780401; DOI=10.1002/pmic.200701057;
RA Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT "Identification of N-linked glycoproteins in human milk by hydrophilic
RT interaction liquid chromatography and mass spectrometry.";
RL Proteomics 8:3833-3847(2008).
RN [30]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-226; ASN-1328 AND ASN-1391.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [31]
RP GLYCOSYLATION AT ASN-1328.
RX PubMed=19139490; DOI=10.1074/mcp.m800504-mcp200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B.,
RA Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L.,
RA Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core fucosylated
RT glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [32]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS], AND STRUCTURE OF CARBOHYDRATES.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G.,
RA Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [33]
RP GLYCOSYLATION AT THR-1244, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures
RT of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
RN [34]
RP PHOSPHORYLATION AT SER-918.
RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028;
RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J.,
RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N.,
RA Pinna L.A., Pagliarini D.J., Dixon J.E.;
RT "A single kinase generates the majority of the secreted phosphoproteome.";
RL Cell 161:1619-1632(2015).
RN [35]
RP POLYMORPHISM, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=26814963; DOI=10.1038/nature16549;
RG Schizophrenia Working Group of the Psychiatric Genomics Consortium;
RA Sekar A., Bialas A.R., de Rivera H., Davis A., Hammond T.R., Kamitaki N.,
RA Tooley K., Presumey J., Baum M., Van Doren V., Genovese G., Rose S.A.,
RA Handsaker R.E., Daly M.J., Carroll M.C., Stevens B., McCarroll S.A.;
RT "Schizophrenia risk from complex variation of complement component 4.";
RL Nature 530:177-183(2016).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 957-1323.
RX PubMed=12367531; DOI=10.1016/s0022-2836(02)00854-9;
RA van den Elsen J.M., Martin A., Wong V., Clemenza L., Rose D.R.,
RA Isenman D.E.;
RT "X-ray crystal structure of the C4d fragment of human complement component
RT C4.";
RL J. Mol. Biol. 322:1103-1115(2002).
RN [37]
RP VARIANT ALA-1286 (ALLOTYPE C4A6).
RX PubMed=1573268;
RA Anderson M.J., Milner C.M., Cotton G.H., Campbell R.D.;
RT "The coding sequence of the hemolytically inactive C4A6 allotype of human
RT complement component C4 reveals that a single arginine to tryptophan
RT substitution at beta-chain residue 458 is the likely cause of the defect.";
RL J. Immunol. 148:2795-2802(1992).
CC -!- FUNCTION: Non-enzymatic component of C3 and C5 convertases and thus
CC essential for the propagation of the classical complement pathway.
CC Covalently binds to immunoglobulins and immune complexes and enhances
CC the solubilization of immune aggregates and the clearance of IC through
CC CR1 on erythrocytes. C4A isotype is responsible for effective binding
CC to form amide bonds with immune aggregates or protein antigens, while
CC C4B isotype catalyzes the transacylation of the thioester carbonyl
CC group to form ester bonds with carbohydrate antigens.
CC -!- FUNCTION: Derived from proteolytic degradation of complement C4, C4a
CC anaphylatoxin is a mediator of local inflammatory process. It induces
CC the contraction of smooth muscle, increases vascular permeability and
CC causes histamine release from mast cells and basophilic leukocytes.
CC -!- SUBUNIT: Circulates in blood as a disulfide-linked trimer of an alpha,
CC beta and gamma chain.
CC -!- SUBCELLULAR LOCATION: Secreted. Synapse {ECO:0000269|PubMed:26814963}.
CC Cell projection, axon {ECO:0000269|PubMed:26814963}. Cell projection,
CC dendrite {ECO:0000269|PubMed:26814963}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P0C0L4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P0C0L4-2; Sequence=VSP_046252;
CC -!- TISSUE SPECIFICITY: Complement component C4 is expressed at highest
CC levels in the liver, at moderate levels in the adrenal cortex, adrenal
CC medulla, thyroid gland, and the kidney, and at lowest levels in the
CC heart, ovary, small intestine, thymus, pancreas and spleen. The extra-
CC hepatic sites of expression may be important for the local protection
CC and inflammatory response. {ECO:0000269|PubMed:11367523}.
CC -!- PTM: Prior to secretion, the single-chain precursor is enzymatically
CC cleaved to yield non-identical chains alpha, beta and gamma. During
CC activation, the alpha chain is cleaved by C1 into C4a and C4b, and C4b
CC stays linked to the beta and gamma chains. Further degradation of C4b
CC by C1 into the inactive fragments C4c and C4d blocks the generation of
CC C3 convertase. The proteolytic cleavages often are incomplete so that
CC many structural forms can be found in plasma.
CC -!- PTM: N- and O-glycosylated. O-glycosylated with a core 1 or possibly
CC core 8 glycan. {ECO:0000269|PubMed:12754519,
CC ECO:0000269|PubMed:14760718, ECO:0000269|PubMed:16335952,
CC ECO:0000269|PubMed:18780401, ECO:0000269|PubMed:19139490,
CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19838169,
CC ECO:0000269|PubMed:23234360}.
CC -!- POLYMORPHISM: The complement component C4 is the most polymorphic
CC protein of the complement system. It is the product of 2 closely linked
CC and highly homologous genes, C4A and C4B. Once polymorphic variation is
CC discounted, the 2 isotypes differ by only 4 amino acids at positions
CC 1120-1125: PCPVLD for C4A and LSPVIH for C4B. The 2 isotypes bear
CC several antigenic determinants defining Chido/Rodgers blood group
CC system [MIM:614374]. Rodgers determinants are generally associated with
CC C4A allotypes, and Chido with C4B. Variations at these loci involve not
CC only nucleotide polymorphisms, but also gene number and gene size. Some
CC individuals may lack either C4A, or C4B gene. Partial deficiency of C4A
CC or C4B is the most commonly inherited immune deficiency known in humans
CC with a combined frequency over 31% in the normal Caucasian population
CC (PubMed:11367523). C4A6 allotype is deficient in hemolytic activity.
CC Allotype C4A13 is infrequent. Common copy-number variants of C4A and
CC C4B affecting expression of complement component C4 in the brain have
CC been associated with schizophrenia risk (PubMed:26814963).
CC {ECO:0000269|PubMed:11367523, ECO:0000269|PubMed:26814963}.
CC -!- DISEASE: Complement component 4A deficiency (C4AD) [MIM:614380]: A rare
CC defect of the complement classical pathway associated with the
CC development of autoimmune disorders, mainly systemic lupus with or
CC without associated glomerulonephritis. {ECO:0000269|PubMed:8473511}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic,
CC relapsing, inflammatory, and often febrile multisystemic disorder of
CC connective tissue, characterized principally by involvement of the
CC skin, joints, kidneys and serosal membranes. It is of unknown etiology,
CC but is thought to represent a failure of the regulatory mechanisms of
CC the autoimmune system. The disease is marked by a wide range of system
CC dysfunctions, an elevated erythrocyte sedimentation rate, and the
CC formation of LE cells in the blood or bone marrow.
CC {ECO:0000269|PubMed:10092831, ECO:0000269|PubMed:17503323}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry. Interindividual copy-number variation
CC (CNV) of complement component C4 and associated polymorphisms result in
CC different susceptibilities to SLE. The risk of SLE susceptibility has
CC been shown to be significantly increased among subjects with only two
CC copies of total C4. A high copy number is a protective factor against
CC SLE.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB59537.1; Type=Miscellaneous discrepancy; Note=During cDNA synthesis, the 5' end has been inverted (PubMed:3838531).; Evidence={ECO:0000305|PubMed:3838531};
CC Sequence=BAE06071.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene mutation
CC database;
CC URL="https://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system=chrg";
CC ---------------------------------------------------------------------------
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DR EMBL; K02403; AAB59537.1; ALT_SEQ; mRNA.
DR EMBL; M59815; AAA51855.1; -; Genomic_DNA.
DR EMBL; M59816; AAA51855.1; JOINED; Genomic_DNA.
DR EMBL; L26261; AAA20121.2; -; Genomic_DNA.
DR EMBL; AB209989; BAE06071.1; ALT_INIT; mRNA.
DR EMBL; AL645922; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL844853; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL929593; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CR936924; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC012372; AAH12372.2; -; mRNA.
DR EMBL; BC063289; AAH63289.1; -; mRNA.
DR EMBL; BC144546; AAI44547.1; -; mRNA.
DR EMBL; BC146673; AAI46674.1; -; mRNA.
DR EMBL; BC146849; AAI46850.1; -; mRNA.
DR EMBL; BC151204; AAI51205.1; -; mRNA.
DR EMBL; BC171786; AAI71786.1; -; mRNA.
DR EMBL; M14824; AAA52292.1; -; Genomic_DNA.
DR EMBL; X77491; CAA54627.1; -; Genomic_DNA.
DR EMBL; AY379925; AAR89152.1; -; Genomic_DNA.
DR EMBL; AY379926; AAR89153.1; -; Genomic_DNA.
DR EMBL; AY379927; AAR89154.1; -; Genomic_DNA.
DR EMBL; AY379928; AAR89155.1; -; Genomic_DNA.
DR EMBL; AY379929; AAR89156.1; -; Genomic_DNA.
DR EMBL; AY379930; AAR89157.1; -; Genomic_DNA.
DR EMBL; AY379931; AAR89158.1; -; Genomic_DNA.
DR EMBL; AY379932; AAR89159.1; -; Genomic_DNA.
DR EMBL; AY379933; AAR89160.1; -; Genomic_DNA.
DR EMBL; AY379934; AAR89161.1; -; Genomic_DNA.
DR EMBL; AY379935; AAR89162.1; -; Genomic_DNA.
DR EMBL; AY379960; AAR89164.1; -; Genomic_DNA.
DR EMBL; AY379962; AAR89166.1; -; Genomic_DNA.
DR EMBL; AY379963; AAR89167.1; -; Genomic_DNA.
DR EMBL; AY379964; AAR89168.1; -; Genomic_DNA.
DR EMBL; AY379965; AAR89169.1; -; Genomic_DNA.
DR EMBL; AY379966; AAR89170.1; -; Genomic_DNA.
DR EMBL; U77886; AAK49810.1; -; Genomic_DNA.
DR EMBL; V00502; CAA23760.1; -; mRNA.
DR EMBL; K00830; AAA36229.1; -; mRNA.
DR CCDS; CCDS47404.1; -. [P0C0L4-1]
DR CCDS; CCDS59005.1; -. [P0C0L4-2]
DR PIR; B20807; B20807.
DR PIR; I56095; C4HU.
DR RefSeq; NP_001002029.3; NM_001002029.3.
DR RefSeq; NP_001239133.1; NM_001252204.1. [P0C0L4-2]
DR RefSeq; NP_009224.2; NM_007293.2. [P0C0L4-1]
DR PDB; 1HZF; X-ray; 2.30 A; A=957-1323.
DR PDB; 4FXG; X-ray; 3.75 A; A/D=20-675, B/E=680-1446, C/F=1454-1744.
DR PDB; 4FXK; X-ray; 3.60 A; A=20-675, B=680-1446, C=1454-1744.
DR PDB; 4XAM; X-ray; 4.20 A; C/E=757-1446, D/F=1454-1744.
DR PDB; 5JPM; X-ray; 3.75 A; A/D=20-675, B/E=680-1446, C/F=1454-1744.
DR PDB; 5JPN; X-ray; 3.60 A; A=20-675, B=680-1446, C=1455-1744.
DR PDB; 5JTW; X-ray; 3.50 A; A/D=20-675, B/E=757-1446, C/F=1454-1744.
DR PDB; 6YSQ; X-ray; 3.30 A; C/D=757-1446.
DR PDBsum; 1HZF; -.
DR PDBsum; 4FXG; -.
DR PDBsum; 4FXK; -.
DR PDBsum; 4XAM; -.
DR PDBsum; 5JPM; -.
DR PDBsum; 5JPN; -.
DR PDBsum; 5JTW; -.
DR PDBsum; 6YSQ; -.
DR AlphaFoldDB; P0C0L4; -.
DR SMR; P0C0L4; -.
DR BioGRID; 107181; 65.
DR BioGRID; 107182; 7.
DR ComplexPortal; CPX-5675; Classical and lectin pathway C3 convertase complex C4b2a-A.
DR IntAct; P0C0L4; 49.
DR STRING; 9606.ENSP00000396688; -.
DR DrugBank; DB00028; Human immunoglobulin G.
DR MEROPS; I39.951; -.
DR CarbonylDB; P0C0L4; -.
DR GlyConnect; 651; 32 N-Linked glycans (4 sites), 4 O-Linked glycans (2 sites).
DR GlyGen; P0C0L4; 8 sites, 35 N-linked glycans (4 sites), 6 O-linked glycans (4 sites).
DR iPTMnet; P0C0L4; -.
DR PhosphoSitePlus; P0C0L4; -.
DR BioMuta; C4A; -.
DR DMDM; 476007827; -.
DR CPTAC; CPTAC-665; -.
DR CPTAC; CPTAC-666; -.
DR EPD; P0C0L4; -.
DR jPOST; P0C0L4; -.
DR MassIVE; P0C0L4; -.
DR MaxQB; P0C0L4; -.
DR PaxDb; P0C0L4; -.
DR PeptideAtlas; P0C0L4; -.
DR PRIDE; P0C0L4; -.
DR ProteomicsDB; 2869; -.
DR ProteomicsDB; 52292; -. [P0C0L4-1]
DR ProteomicsDB; 62992; -.
DR ProteomicsDB; 774; -.
DR Antibodypedia; 34827; 695 antibodies from 37 providers.
DR DNASU; 721; -.
DR Ensembl; ENST00000383325.8; ENSP00000372815.4; ENSG00000206340.10.
DR Ensembl; ENST00000421274.6; ENSP00000388662.2; ENSG00000227746.9.
DR Ensembl; ENST00000428956.7; ENSP00000396688.2; ENSG00000244731.8. [P0C0L4-1]
DR Ensembl; ENST00000498271.1; ENSP00000420212.1; ENSG00000244731.8. [P0C0L4-2]
DR GeneID; 720; -.
DR GeneID; 721; -.
DR KEGG; hsa:720; -.
DR KEGG; hsa:721; -.
DR MANE-Select; ENST00000428956.7; ENSP00000396688.2; NM_007293.3; NP_009224.2.
DR UCSC; uc011doy.3; human. [P0C0L4-1]
DR CTD; 720; -.
DR CTD; 721; -.
DR DisGeNET; 720; -.
DR DisGeNET; 721; -.
DR GeneCards; C4A; -.
DR HGNC; HGNC:1323; C4A.
DR HPA; ENSG00000244731; Tissue enhanced (adrenal gland, liver).
DR MalaCards; C4A; -.
DR MIM; 120790; phenotype.
DR MIM; 120810; gene.
DR MIM; 152700; phenotype.
DR MIM; 614374; phenotype.
DR MIM; 614380; phenotype.
DR neXtProt; NX_P0C0L4; -.
DR NIAGADS; ENSG00000244731; -.
DR OpenTargets; ENSG00000244731; -.
DR Orphanet; 300345; Autosomal systemic lupus erythematosus.
DR Orphanet; 117; Behcet disease.
DR Orphanet; 169147; Immunodeficiency due to a classical component pathway complement deficiency.
DR Orphanet; 536; Systemic lupus erythematosus.
DR PharmGKB; PA25903; -.
DR PharmGKB; PA25904; -.
DR VEuPathDB; HostDB:ENSG00000244731; -.
DR eggNOG; KOG1366; Eukaryota.
DR GeneTree; ENSGT00940000155739; -.
DR HOGENOM; CLU_001634_4_1_1; -.
DR InParanoid; P0C0L4; -.
DR OMA; PSEKNCQ; -.
DR OrthoDB; 28894at2759; -.
DR PhylomeDB; P0C0L4; -.
DR TreeFam; TF313285; -.
DR PathwayCommons; P0C0L4; -.
DR Reactome; R-HSA-166663; Initial triggering of complement.
DR Reactome; R-HSA-174577; Activation of C3 and C5.
DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
DR Reactome; R-HSA-977606; Regulation of Complement cascade.
DR SABIO-RK; P0C0L4; -.
DR SignaLink; P0C0L4; -.
DR SIGNOR; P0C0L4; -.
DR BioGRID-ORCS; 720; 30 hits in 1046 CRISPR screens.
DR BioGRID-ORCS; 721; 8 hits in 671 CRISPR screens.
DR ChiTaRS; C4A; human.
DR EvolutionaryTrace; P0C0L4; -.
DR GeneWiki; C4A; -.
DR Pharos; P0C0L4; Tbio.
DR PRO; PR:P0C0L4; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; P0C0L4; protein.
DR Bgee; ENSG00000244731; Expressed in right lobe of liver and 92 other tissues.
DR Genevisible; P0C0L4; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IDA:UniProtKB.
DR GO; GO:0072562; C:blood microparticle; HDA:UniProtKB.
DR GO; GO:0005601; C:classical-complement-pathway C3/C5 convertase complex; IPI:ComplexPortal.
DR GO; GO:0030425; C:dendrite; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045202; C:synapse; IDA:UniProtKB.
DR GO; GO:0001849; F:complement component C1q complex binding; IDA:BHF-UCL.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0006956; P:complement activation; IDA:ComplexPortal.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:2000427; P:positive regulation of apoptotic cell clearance; IGI:BHF-UCL.
DR GO; GO:0050778; P:positive regulation of immune response; IC:ComplexPortal.
DR GO; GO:1903028; P:positive regulation of opsonization; IC:ComplexPortal.
DR CDD; cd00017; ANATO; 1.
DR Gene3D; 2.40.50.120; -; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR Gene3D; 2.60.40.690; -; 1.
DR InterPro; IPR009048; A-macroglobulin_rcpt-bd.
DR InterPro; IPR036595; A-macroglobulin_rcpt-bd_sf.
DR InterPro; IPR011625; A2M_N_BRD.
DR InterPro; IPR011626; Alpha-macroglobulin_TED.
DR InterPro; IPR000020; Anaphylatoxin/fibulin.
DR InterPro; IPR018081; Anaphylatoxin_comp_syst.
DR InterPro; IPR001840; Anaphylatoxn_comp_syst_dom.
DR InterPro; IPR037569; Complement_C4A.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR001599; Macroglobln_a2.
DR InterPro; IPR019742; MacrogloblnA2_CS.
DR InterPro; IPR002890; MG2.
DR InterPro; IPR041555; MG3.
DR InterPro; IPR040839; MG4.
DR InterPro; IPR001134; Netrin_domain.
DR InterPro; IPR018933; Netrin_module_non-TIMP.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR InterPro; IPR008993; TIMP-like_OB-fold.
DR PANTHER; PTHR11412:SF86; PTHR11412:SF86; 1.
DR Pfam; PF00207; A2M; 1.
DR Pfam; PF07703; A2M_BRD; 1.
DR Pfam; PF07677; A2M_recep; 1.
DR Pfam; PF01821; ANATO; 1.
DR Pfam; PF01835; MG2; 1.
DR Pfam; PF17791; MG3; 1.
DR Pfam; PF17789; MG4; 1.
DR Pfam; PF01759; NTR; 1.
DR Pfam; PF07678; TED_complement; 1.
DR PRINTS; PR00004; ANAPHYLATOXN.
DR SMART; SM01360; A2M; 1.
DR SMART; SM01359; A2M_N_2; 1.
DR SMART; SM01361; A2M_recep; 1.
DR SMART; SM00104; ANATO; 1.
DR SMART; SM00643; C345C; 1.
DR SUPFAM; SSF47686; SSF47686; 1.
DR SUPFAM; SSF48239; SSF48239; 1.
DR SUPFAM; SSF49410; SSF49410; 1.
DR SUPFAM; SSF50242; SSF50242; 1.
DR PROSITE; PS00477; ALPHA_2_MACROGLOBULIN; 1.
DR PROSITE; PS01177; ANAPHYLATOXIN_1; 1.
DR PROSITE; PS01178; ANAPHYLATOXIN_2; 1.
DR PROSITE; PS50189; NTR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Blood group antigen; Cell projection;
KW Cleavage on pair of basic residues; Complement pathway;
KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein;
KW Immunity; Inflammatory response; Innate immunity; Phosphoprotein;
KW Reference proteome; Secreted; Signal; Sulfation; Synapse;
KW Systemic lupus erythematosus; Thioester bond.
FT SIGNAL 1..19
FT CHAIN 20..675
FT /note="Complement C4 beta chain"
FT /id="PRO_0000005966"
FT PROPEP 676..679
FT /evidence="ECO:0000269|PubMed:6167582"
FT /id="PRO_0000005967"
FT CHAIN 680..1446
FT /note="Complement C4-A alpha chain"
FT /id="PRO_0000005968"
FT CHAIN 680..756
FT /note="C4a anaphylatoxin"
FT /id="PRO_0000005969"
FT CHAIN 757..1446
FT /note="C4b-A"
FT /id="PRO_0000005970"
FT CHAIN 957..1336
FT /note="C4d-A"
FT /id="PRO_0000042698"
FT PROPEP 1447..1453
FT /id="PRO_0000005971"
FT CHAIN 1454..1744
FT /note="Complement C4 gamma chain"
FT /id="PRO_0000005972"
FT DOMAIN 702..736
FT /note="Anaphylatoxin-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00022"
FT DOMAIN 1595..1742
FT /note="NTR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT SITE 1125
FT /note="Responsible for effective binding to form amide
FT bonds with immune aggregates or protein antigens"
FT MOD_RES 918
FT /note="Phosphoserine; by FAM20C"
FT /evidence="ECO:0000269|PubMed:26091039"
FT MOD_RES 1417
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000269|PubMed:3944109"
FT MOD_RES 1420
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000269|PubMed:3944109"
FT MOD_RES 1422
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000269|PubMed:3944109"
FT CARBOHYD 226
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12754519,
FT ECO:0000269|PubMed:18780401, ECO:0000269|PubMed:19159218"
FT CARBOHYD 862
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT CARBOHYD 1244
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:23234360"
FT CARBOHYD 1328
FT /note="N-linked (GlcNAc...) (complex) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:18780401, ECO:0000269|PubMed:19139490,
FT ECO:0000269|PubMed:19159218"
FT CARBOHYD 1391
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14760718,
FT ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:19159218"
FT DISULFID 702..728
FT /evidence="ECO:0000250"
FT DISULFID 703..735
FT /evidence="ECO:0000250"
FT DISULFID 716..736
FT /evidence="ECO:0000250"
FT DISULFID 1595..1673
FT /evidence="ECO:0000250"
FT DISULFID 1618..1742
FT /evidence="ECO:0000250"
FT CROSSLNK 1010..1013
FT /note="Isoglutamyl cysteine thioester (Cys-Gln)"
FT VAR_SEQ 1458..1503
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_046252"
FT VARIANT 141
FT /note="L -> V (in dbSNP:rs9296005)"
FT /id="VAR_069154"
FT VARIANT 347
FT /note="S -> Y (in allotype C4A3a, allotype C4A6;
FT dbSNP:rs392610)"
FT /evidence="ECO:0000269|PubMed:14574404,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:1988494"
FT /id="VAR_019778"
FT VARIANT 418
FT /note="V -> A (in allotype C4A4)"
FT /evidence="ECO:0000269|PubMed:6546707"
FT /id="VAR_069155"
FT VARIANT 477
FT /note="R -> W (in allotype C4A6)"
FT /evidence="ECO:0000269|Ref.8"
FT /id="VAR_001987"
FT VARIANT 549
FT /note="H -> P (in dbSNP:rs2229405)"
FT /evidence="ECO:0000269|Ref.8"
FT /id="VAR_069156"
FT VARIANT 726
FT /note="P -> L (in allotype C4A3a; dbSNP:rs1215093373)"
FT /evidence="ECO:0000269|PubMed:1988494"
FT /id="VAR_001988"
FT VARIANT 727
FT /note="D -> N"
FT /evidence="ECO:0000269|PubMed:8012361"
FT /id="VAR_019779"
FT VARIANT 907
FT /note="A -> T (in dbSNP:rs429329)"
FT /evidence="ECO:0000269|Ref.8"
FT /id="VAR_019780"
FT VARIANT 1073
FT /note="D -> G (in allotype C4A1, allotype C4A2;
FT dbSNP:rs147162052)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:3696167, ECO:0000269|Ref.8"
FT /id="VAR_069158"
FT VARIANT 1176
FT /note="N -> S (in allotype C4A1; dbSNP:rs17874654)"
FT /evidence="ECO:0000269|PubMed:14574404,
FT ECO:0000269|PubMed:3696167, ECO:0000269|Ref.3,
FT ECO:0000269|Ref.8"
FT /id="VAR_069159"
FT VARIANT 1201
FT /note="T -> S (in allotype C4A4)"
FT /evidence="ECO:0000269|PubMed:6546707"
FT /id="VAR_001992"
FT VARIANT 1207
FT /note="V -> A (in allotype C4A1, allotype C4A13;
FT dbSNP:rs28357075)"
FT /evidence="ECO:0000269|PubMed:3696167,
FT ECO:0000269|PubMed:6832377, ECO:0000269|Ref.8"
FT /id="VAR_001993"
FT VARIANT 1210
FT /note="L -> R (in allotype C4A1, allotype C4A13;
FT dbSNP:rs28357076)"
FT /evidence="ECO:0000269|PubMed:3696167,
FT ECO:0000269|PubMed:6832377, ECO:0000269|Ref.8"
FT /id="VAR_001994"
FT VARIANT 1286
FT /note="S -> A (in allotype C4A1, allotype C4A3a, allotype
FT C4A6; dbSNP:rs201016130)"
FT /evidence="ECO:0000269|PubMed:14574404,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:1988494,
FT ECO:0000269|PubMed:3696167, ECO:0000269|PubMed:6832377,
FT ECO:0000269|Ref.3"
FT /id="VAR_001995"
FT CONFLICT 217
FT /note="A -> V (in Ref. 5; AAI71786)"
FT /evidence="ECO:0000305"
FT CONFLICT 643
FT /note="A -> S (in Ref. 5; AAH63289)"
FT /evidence="ECO:0000305"
FT CONFLICT 729
FT /note="R -> W (in Ref. 5; AAH63289)"
FT /evidence="ECO:0000305"
FT CONFLICT 1013
FT /note="Q -> E (in Ref. 11; AA sequence, 12; AA sequence and
FT 13; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1109..1110
FT /note="SQ -> IA (in Ref. 12; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1182
FT /note="K -> I (in Ref. 5; AAH63289)"
FT /evidence="ECO:0000305"
FT CONFLICT 1245
FT /note="P -> Q (in Ref. 5; AAH63289)"
FT /evidence="ECO:0000305"
FT CONFLICT 1271
FT /note="H -> V (in Ref. 12; AA sequence and 16; AA
FT sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1300
FT /note="R -> V (in Ref. 12; AA sequence and 16; AA
FT sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1419..1421
FT /note="Missing (in Ref. 1; AAB59537)"
FT /evidence="ECO:0000305"
FT CONFLICT 1635
FT /note="D -> G (in Ref. 5; AAH12372)"
FT /evidence="ECO:0000305"
FT CONFLICT 1637
FT /note="R -> S (in Ref. 5; AAI44547/AAI46850)"
FT /evidence="ECO:0000305"
FT CONFLICT 1678
FT /note="E -> G (in Ref. 5; AAI71786)"
FT /evidence="ECO:0000305"
FT CONFLICT 1704
FT /note="D -> E (in Ref. 5; AAH12372)"
FT /evidence="ECO:0000305"
FT STRAND 22..32
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 37..45
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 51..59
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 67..69
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 72..77
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 82..87
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 91..97
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 99..101
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 107..113
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 116..119
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 126..135
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 139..146
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 155..163
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 167..169
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 174..179
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 181..183
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 185..191
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 194..203
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 210..221
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 228..233
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 240..253
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 262..270
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 278..287
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 289..291
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 293..295
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 301..304
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 309..314
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 316..325
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 330..332
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 337..346
FT /evidence="ECO:0007829|PDB:5JTW"
FT TURN 347..349
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 352..357
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 361..364
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 366..370
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 372..374
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 382..392
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 395..397
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 402..409
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 412..414
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 417..424
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 430..436
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 442..450
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 452..454
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 456..463
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 472..476
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 488..498
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 504..511
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 514..522
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 527..532
FT /evidence="ECO:0007829|PDB:5JTW"
FT TURN 535..537
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 539..549
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 552..561
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 571..575
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 586..605
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 607..611
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 621..628
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 629..631
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 643..650
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 652..655
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 657..660
FT /evidence="ECO:0007829|PDB:5JTW"
FT TURN 666..668
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 780..782
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 786..798
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 804..814
FT /evidence="ECO:0007829|PDB:6YSQ"
FT TURN 815..817
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 818..821
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 825..829
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 832..837
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 849..851
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 853..857
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 859..861
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 863..869
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 875..877
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 878..880
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 885..889
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 894..896
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 899..903
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 906..921
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 924..934
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 936..948
FT /evidence="ECO:0007829|PDB:6YSQ"
FT TURN 950..953
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 954..960
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 973..981
FT /evidence="ECO:0007829|PDB:6YSQ"
FT HELIX 997..1001
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1011..1030
FT /evidence="ECO:0007829|PDB:1HZF"
FT STRAND 1035..1037
FT /evidence="ECO:0007829|PDB:6YSQ"
FT HELIX 1041..1057
FT /evidence="ECO:0007829|PDB:1HZF"
FT TURN 1062..1064
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1068..1072
FT /evidence="ECO:0007829|PDB:6YSQ"
FT HELIX 1076..1089
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1090..1092
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1097..1107
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1108..1110
FT /evidence="ECO:0007829|PDB:1HZF"
FT STRAND 1113..1115
FT /evidence="ECO:0007829|PDB:6YSQ"
FT HELIX 1126..1132
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1137..1153
FT /evidence="ECO:0007829|PDB:1HZF"
FT TURN 1158..1161
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1162..1185
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1190..1202
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1207..1218
FT /evidence="ECO:0007829|PDB:1HZF"
FT STRAND 1225..1228
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1259..1275
FT /evidence="ECO:0007829|PDB:1HZF"
FT STRAND 1276..1278
FT /evidence="ECO:0007829|PDB:6YSQ"
FT HELIX 1280..1292
FT /evidence="ECO:0007829|PDB:1HZF"
FT HELIX 1294..1297
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1302..1319
FT /evidence="ECO:0007829|PDB:1HZF"
FT STRAND 1326..1335
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1338..1350
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1354..1356
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1362..1364
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1366..1370
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1372..1374
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1376..1386
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1395..1405
FT /evidence="ECO:0007829|PDB:6YSQ"
FT STRAND 1409..1411
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1465..1475
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1484..1489
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1494..1496
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1498..1506
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1511..1518
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1521..1527
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1534..1544
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1552..1560
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1564..1570
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1573..1575
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1581..1584
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1587..1590
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1613..1618
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1624..1637
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1640..1652
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1664..1670
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1681..1687
FT /evidence="ECO:0007829|PDB:5JTW"
FT STRAND 1708..1711
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1716..1719
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1721..1723
FT /evidence="ECO:0007829|PDB:5JTW"
FT HELIX 1726..1740
FT /evidence="ECO:0007829|PDB:5JTW"
SQ SEQUENCE 1744 AA; 192785 MW; 9396A4CC4DA3602C CRC64;
MRLLWGLIWA SSFFTLSLQK PRLLLFSPSV VHLGVPLSVG VQLQDVPRGQ VVKGSVFLRN
PSRNNVPCSP KVDFTLSSER DFALLSLQVP LKDAKSCGLH QLLRGPEVQL VAHSPWLKDS
LSRTTNIQGI NLLFSSRRGH LFLQTDQPIY NPGQRVRYRV FALDQKMRPS TDTITVMVEN
SHGLRVRKKE VYMPSSIFQD DFVIPDISEP GTWKISARFS DGLESNSSTQ FEVKKYVLPN
FEVKITPGKP YILTVPGHLD EMQLDIQARY IYGKPVQGVA YVRFGLLDED GKKTFFRGLE
SQTKLVNGQS HISLSKAEFQ DALEKLNMGI TDLQGLRLYV AAAIIESPGG EMEEAELTSW
YFVSSPFSLD LSKTKRHLVP GAPFLLQALV REMSGSPASG IPVKVSATVS SPGSVPEVQD
IQQNTDGSGQ VSIPIIIPQT ISELQLSVSA GSPHPAIARL TVAAPPSGGP GFLSIERPDS
RPPRVGDTLN LNLRAVGSGA TFSHYYYMIL SRGQIVFMNR EPKRTLTSVS VFVDHHLAPS
FYFVAFYYHG DHPVANSLRV DVQAGACEGK LELSVDGAKQ YRNGESVKLH LETDSLALVA
LGALDTALYA AGSKSHKPLN MGKVFEAMNS YDLGCGPGGG DSALQVFQAA GLAFSDGDQW
TLSRKRLSCP KEKTTRKKRN VNFQKAINEK LGQYASPTAK RCCQDGVTRL PMMRSCEQRA
ARVQQPDCRE PFLSCCQFAE SLRKKSRDKG QAGLQRALEI LQEEDLIDED DIPVRSFFPE
NWLWRVETVD RFQILTLWLP DSLTTWEIHG LSLSKTKGLC VATPVQLRVF REFHLHLRLP
MSVRRFEQLE LRPVLYNYLD KNLTVSVHVS PVEGLCLAGG GGLAQQVLVP AGSARPVAFS
VVPTAAAAVS LKVVARGSFE FPVGDAVSKV LQIEKEGAIH REELVYELNP LDHRGRTLEI
PGNSDPNMIP DGDFNSYVRV TASDPLDTLG SEGALSPGGV ASLLRLPRGC GEQTMIYLAP
TLAASRYLDK TEQWSTLPPE TKDHAVDLIQ KGYMRIQQFR KADGSYAAWL SRDSSTWLTA
FVLKVLSLAQ EQVGGSPEKL QETSNWLLSQ QQADGSFQDP CPVLDRSMQG GLVGNDETVA
LTAFVTIALH HGLAVFQDEG AEPLKQRVEA SISKANSFLG EKASAGLLGA HAAAITAYAL
TLTKAPVDLL GVAHNNLMAM AQETGDNLYW GSVTGSQSNA VSPTPAPRNP SDPMPQAPAL
WIETTAYALL HLLLHEGKAE MADQASAWLT RQGSFQGGFR STQDTVIALD ALSAYWIASH
TTEERGLNVT LSSTGRNGFK SHALQLNNRQ IRGLEEELQF SLGSKINVKV GGNSKGTLKV
LRTYNVLDMK NTTCQDLQIE VTVKGHVEYT MEANEDYEDY EYDELPAKDD PDAPLQPVTP
LQLFEGRRNR RRREAPKVVE EQESRVHYTV CIWRNGKVGL SGMAIADVTL LSGFHALRAD
LEKLTSLSDR YVSHFETEGP HVLLYFDSVP TSRECVGFEA VQEVPVGLVQ PASATLYDYY
NPERRCSVFY GAPSKSRLLA TLCSAEVCQC AEGKCPRQRR ALERGLQDED GYRMKFACYY
PRVEYGFQVK VLREDSRAAF RLFETKITQV LHFTKDVKAA ANQMRNFLVR ASCRLRLEPG
KEYLIMGLDG ATYDLEGHPQ YLLDSNSWIE EMPSERLCRS TRQRAACAQL NDFLQEYGTQ
GCQV
