Full text data of C4BPA
C4BPA
(C4BP)
[Confidence: low (only semi-automatic identification from reviews)]
C4b-binding protein alpha chain; C4bp (Proline-rich protein; PRP; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
C4b-binding protein alpha chain; C4bp (Proline-rich protein; PRP; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P04003
ID C4BPA_HUMAN Reviewed; 597 AA.
AC P04003;
DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1993, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=C4b-binding protein alpha chain;
DE Short=C4bp;
DE AltName: Full=Proline-rich protein;
DE Short=PRP;
DE Flags: Precursor;
GN Name=C4BPA; Synonyms=C4BP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=2590215; DOI=10.1016/0006-291X(89)91045-0;
RA Matsuguchi T., Okamura S., Aso T., Sata T., Niho Y.;
RT "Molecular cloning of the cDNA coding for proline-rich protein (PRP):
RT identity of PRP as C4b-binding protein.";
RL Biochem. Biophys. Res. Commun. 165:138-144(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=1989602; DOI=10.1016/0006-291X(91)90509-6;
RA Aso T., Okamura S., Matsuguchi T., Sakamoto N., Sata T., Niho Y.;
RT "Genomic organization of the alpha chain of the human C4b-binding
RT protein gene.";
RL Biochem. Biophys. Res. Commun. 174:222-227(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-81.
RX PubMed=3378624; DOI=10.1016/0014-5793(88)80763-4;
RA Lintin S.J., Lewin A.R., Reid K.B.M.;
RT "Derivation of the sequence of the signal peptide in human C4b-binding
RT protein and interspecies cross-hybridisation of the C4bp cDNA
RT sequence.";
RL FEBS Lett. 232:328-332(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 203-288.
RX PubMed=3017751; DOI=10.1016/0014-5793(86)81390-4;
RA Lintin S.J., Reid K.B.M.;
RT "Studies on the structure of the human C4b-binding protein gene.";
RL FEBS Lett. 204:77-81(1986).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 80-597.
RX PubMed=3840370;
RA Chung L.P., Bentley D.R., Reid K.B.M.;
RT "Molecular cloning and characterization of the cDNA coding for C4b-
RT binding protein, a regulatory protein of the classical pathway of the
RT human complement system.";
RL Biochem. J. 230:133-141(1985).
RN [7]
RP PROTEIN SEQUENCE OF 49-88.
RX PubMed=4033666; DOI=10.1016/0161-5890(85)90127-0;
RA Chung L.P., Gagnon J., Reid K.B.M.;
RT "Amino acid sequence studies of human C4b-binding protein: N-terminal
RT sequence analysis and alignment of the fragments produced by limited
RT proteolysis with chymotrypsin and the peptides produced by cyanogen
RT bromide treatment.";
RL Mol. Immunol. 22:427-435(1985).
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-506 AND ASN-528, AND MASS
RP SPECTROMETRY.
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 [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-221 AND ASN-506, AND MASS
RP SPECTROMETRY.
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.,
RA Moore R.J., 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 [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-221 AND ASN-506, AND MASS
RP SPECTROMETRY.
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
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [11]
RP STRUCTURE BY ELECTRON MICROSCOPY, AND LIGAND-BINDING.
RX PubMed=6222381; DOI=10.1073/pnas.80.11.3461;
RA Dahlback B., Smith C.A., Mueller-Eberhard H.J.;
RT "Visualization of human C4b-binding protein and its complexes with
RT vitamin K-dependent protein S and complement protein C4b.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:3461-3465(1983).
CC -!- FUNCTION: Controls the classical pathway of complement activation.
CC It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then
CC hydrolyzes the complement fragment C4b. It also accelerates the
CC degradation of the C4bC2a complex (C3 convertase) by dissociating
CC the complement fragment C2a. Alpha chain binds C4b. It interacts
CC also with anticoagulant protein S and with serum amyloid P
CC component.
CC -!- SUBUNIT: Disulfide-linked complex of alpha and beta chains of 3
CC possible sorts: a 570 kDa complex of 7 alpha chains and 1 beta
CC chain, a 530 kDa homoheptamer of alpha chains or a 500 kDa complex
CC of 6 alpha chains and 1 beta chain. The central body of the alpha
CC chain homopolymer supports tentacles, each with the binding site
CC for C4b at the end.
CC -!- INTERACTION:
CC P13050:arp4 (xeno); NbExp=5; IntAct=EBI-978348, EBI-978341;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Chylomicrons in the plasma.
CC -!- SIMILARITY: Contains 8 Sushi (CCP/SCR) domains.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-17 is the initiator.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M31452; AAA36507.1; -; mRNA.
DR EMBL; M62486; AAA36506.1; -; Genomic_DNA.
DR EMBL; M62475; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62476; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62477; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62478; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62479; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62480; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62481; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62482; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62484; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62485; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; BC022312; AAH22312.1; -; mRNA.
DR EMBL; X07853; CAA30701.1; -; mRNA.
DR EMBL; X04284; CAB51244.1; -; Genomic_DNA.
DR EMBL; X04296; CAA27839.1; -; Genomic_DNA.
DR EMBL; X02865; CAA26617.1; -; mRNA.
DR PIR; A33568; NBHUC4.
DR RefSeq; NP_000706.1; NM_000715.3.
DR RefSeq; XP_005273308.1; XM_005273251.1.
DR RefSeq; XP_005273309.1; XM_005273252.1.
DR UniGene; Hs.1012; -.
DR PDB; 2A55; NMR; -; A=49-172.
DR PDB; 4B0F; X-ray; 2.80 A; A/B/C/D/E/F/G=540-597.
DR PDBsum; 2A55; -.
DR PDBsum; 4B0F; -.
DR ProteinModelPortal; P04003; -.
DR SMR; P04003; 49-597.
DR IntAct; P04003; 6.
DR STRING; 9606.ENSP00000356037; -.
DR PhosphoSite; P04003; -.
DR DMDM; 416733; -.
DR PaxDb; P04003; -.
DR PeptideAtlas; P04003; -.
DR PRIDE; P04003; -.
DR DNASU; 722; -.
DR Ensembl; ENST00000367070; ENSP00000356037; ENSG00000123838.
DR GeneID; 722; -.
DR KEGG; hsa:722; -.
DR UCSC; uc001hfo.3; human.
DR CTD; 722; -.
DR GeneCards; GC01P207277; -.
DR HGNC; HGNC:1325; C4BPA.
DR HPA; HPA000926; -.
DR HPA; HPA001578; -.
DR MIM; 120830; gene.
DR neXtProt; NX_P04003; -.
DR PharmGKB; PA25905; -.
DR eggNOG; NOG150577; -.
DR HOGENOM; HOG000015324; -.
DR HOVERGEN; HBG004657; -.
DR InParanoid; P04003; -.
DR KO; K04002; -.
DR OMA; VENETIG; -.
DR OrthoDB; EOG725DH2; -.
DR PhylomeDB; P04003; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P04003; -.
DR GenomeRNAi; 722; -.
DR NextBio; 2938; -.
DR PRO; PR:P04003; -.
DR ArrayExpress; P04003; -.
DR Bgee; P04003; -.
DR CleanEx; HS_C4BPA; -.
DR Genevestigator; P04003; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR InterPro; IPR000436; Sushi_SCR_CCP.
DR Pfam; PF00084; Sushi; 8.
DR SMART; SM00032; CCP; 8.
DR SUPFAM; SSF57535; SSF57535; 8.
DR PROSITE; PS50923; SUSHI; 8.
PE 1: Evidence at protein level;
KW 3D-structure; Complement pathway; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity;
KW Innate immunity; Polymorphism; Reference proteome; Repeat; Secreted;
KW Signal; Sushi.
FT SIGNAL 1 48
FT CHAIN 49 597 C4b-binding protein alpha chain.
FT /FTId=PRO_0000005888.
FT DOMAIN 49 110 Sushi 1.
FT DOMAIN 111 172 Sushi 2.
FT DOMAIN 173 236 Sushi 3.
FT DOMAIN 237 296 Sushi 4.
FT DOMAIN 297 362 Sushi 5.
FT DOMAIN 363 424 Sushi 6.
FT DOMAIN 425 482 Sushi 7.
FT DOMAIN 483 540 Sushi 8.
FT CARBOHYD 221 221 N-linked (GlcNAc...).
FT CARBOHYD 506 506 N-linked (GlcNAc...).
FT CARBOHYD 528 528 N-linked (GlcNAc...).
FT DISULFID 50 96 By similarity.
FT DISULFID 81 108 By similarity.
FT DISULFID 113 154 By similarity.
FT DISULFID 140 170 By similarity.
FT DISULFID 175 217 By similarity.
FT DISULFID 203 234 By similarity.
FT DISULFID 239 281 By similarity.
FT DISULFID 267 294 By similarity.
FT DISULFID 299 348 By similarity.
FT DISULFID 332 360 By similarity.
FT DISULFID 365 409 By similarity.
FT DISULFID 399 422 By similarity.
FT DISULFID 426 468 By similarity.
FT DISULFID 454 480 By similarity.
FT DISULFID 484 525 By similarity.
FT DISULFID 511 538 By similarity.
FT DISULFID 546 546 Interchain (with beta chain) (Potential).
FT DISULFID 558 558 Interchain (with beta chain) (Potential).
FT VARIANT 4 4 P -> Q (in dbSNP:rs55867570).
FT /FTId=VAR_061123.
FT VARIANT 60 60 A -> V (in dbSNP:rs17020956).
FT /FTId=VAR_048815.
FT VARIANT 240 240 R -> H (in dbSNP:rs45574833).
FT /FTId=VAR_061124.
FT VARIANT 300 300 I -> T (in dbSNP:rs4844573).
FT /FTId=VAR_024420.
FT VARIANT 357 357 Y -> H.
FT /FTId=VAR_001978.
FT VARIANT 473 473 W -> L (in dbSNP:rs1801341).
FT /FTId=VAR_012038.
FT STRAND 85 87
FT STRAND 98 103
FT STRAND 108 110
FT STRAND 131 133
FT STRAND 158 160
FT HELIX 547 555
FT STRAND 558 561
FT HELIX 562 589
FT HELIX 591 596
SQ SEQUENCE 597 AA; 67033 MW; 67E03F2EA85A16DD CRC64;
MHPPKTPSGA LHRKRKMAAW PFSRLWKVSD PILFQMTLIA ALLPAVLGNC GPPPTLSFAA
PMDITLTETR FKTGTTLKYT CLPGYVRSHS TQTLTCNSDG EWVYNTFCIY KRCRHPGELR
NGQVEIKTDL SFGSQIEFSC SEGFFLIGST TSRCEVQDRG VGWSHPLPQC EIVKCKPPPD
IRNGRHSGEE NFYAYGFSVT YSCDPRFSLL GHASISCTVE NETIGVWRPS PPTCEKITCR
KPDVSHGEMV SGFGPIYNYK DTIVFKCQKG FVLRGSSVIH CDADSKWNPS PPACEPNSCI
NLPDIPHASW ETYPRPTKED VYVVGTVLRY RCHPGYKPTT DEPTTVICQK NLRWTPYQGC
EALCCPEPKL NNGEITQHRK SRPANHCVYF YGDEISFSCH ETSRFSAICQ GDGTWSPRTP
SCGDICNFPP KIAHGHYKQS SSYSFFKEEI IYECDKGYIL VGQAKLSCSY SHWSAPAPQC
KALCRKPELV NGRLSVDKDQ YVEPENVTIQ CDSGYGVVGP QSITCSGNRT WYPEVPKCEW
ETPEGCEQVL TGKRLMQCLP NPEDVKMALE VYKLSLEIEQ LELQRDSARQ STLDKEL
//
ID C4BPA_HUMAN Reviewed; 597 AA.
AC P04003;
DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1993, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=C4b-binding protein alpha chain;
DE Short=C4bp;
DE AltName: Full=Proline-rich protein;
DE Short=PRP;
DE Flags: Precursor;
GN Name=C4BPA; Synonyms=C4BP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=2590215; DOI=10.1016/0006-291X(89)91045-0;
RA Matsuguchi T., Okamura S., Aso T., Sata T., Niho Y.;
RT "Molecular cloning of the cDNA coding for proline-rich protein (PRP):
RT identity of PRP as C4b-binding protein.";
RL Biochem. Biophys. Res. Commun. 165:138-144(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=1989602; DOI=10.1016/0006-291X(91)90509-6;
RA Aso T., Okamura S., Matsuguchi T., Sakamoto N., Sata T., Niho Y.;
RT "Genomic organization of the alpha chain of the human C4b-binding
RT protein gene.";
RL Biochem. Biophys. Res. Commun. 174:222-227(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-81.
RX PubMed=3378624; DOI=10.1016/0014-5793(88)80763-4;
RA Lintin S.J., Lewin A.R., Reid K.B.M.;
RT "Derivation of the sequence of the signal peptide in human C4b-binding
RT protein and interspecies cross-hybridisation of the C4bp cDNA
RT sequence.";
RL FEBS Lett. 232:328-332(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 203-288.
RX PubMed=3017751; DOI=10.1016/0014-5793(86)81390-4;
RA Lintin S.J., Reid K.B.M.;
RT "Studies on the structure of the human C4b-binding protein gene.";
RL FEBS Lett. 204:77-81(1986).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 80-597.
RX PubMed=3840370;
RA Chung L.P., Bentley D.R., Reid K.B.M.;
RT "Molecular cloning and characterization of the cDNA coding for C4b-
RT binding protein, a regulatory protein of the classical pathway of the
RT human complement system.";
RL Biochem. J. 230:133-141(1985).
RN [7]
RP PROTEIN SEQUENCE OF 49-88.
RX PubMed=4033666; DOI=10.1016/0161-5890(85)90127-0;
RA Chung L.P., Gagnon J., Reid K.B.M.;
RT "Amino acid sequence studies of human C4b-binding protein: N-terminal
RT sequence analysis and alignment of the fragments produced by limited
RT proteolysis with chymotrypsin and the peptides produced by cyanogen
RT bromide treatment.";
RL Mol. Immunol. 22:427-435(1985).
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-506 AND ASN-528, AND MASS
RP SPECTROMETRY.
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 [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-221 AND ASN-506, AND MASS
RP SPECTROMETRY.
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.,
RA Moore R.J., 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 [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-221 AND ASN-506, AND MASS
RP SPECTROMETRY.
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
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [11]
RP STRUCTURE BY ELECTRON MICROSCOPY, AND LIGAND-BINDING.
RX PubMed=6222381; DOI=10.1073/pnas.80.11.3461;
RA Dahlback B., Smith C.A., Mueller-Eberhard H.J.;
RT "Visualization of human C4b-binding protein and its complexes with
RT vitamin K-dependent protein S and complement protein C4b.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:3461-3465(1983).
CC -!- FUNCTION: Controls the classical pathway of complement activation.
CC It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then
CC hydrolyzes the complement fragment C4b. It also accelerates the
CC degradation of the C4bC2a complex (C3 convertase) by dissociating
CC the complement fragment C2a. Alpha chain binds C4b. It interacts
CC also with anticoagulant protein S and with serum amyloid P
CC component.
CC -!- SUBUNIT: Disulfide-linked complex of alpha and beta chains of 3
CC possible sorts: a 570 kDa complex of 7 alpha chains and 1 beta
CC chain, a 530 kDa homoheptamer of alpha chains or a 500 kDa complex
CC of 6 alpha chains and 1 beta chain. The central body of the alpha
CC chain homopolymer supports tentacles, each with the binding site
CC for C4b at the end.
CC -!- INTERACTION:
CC P13050:arp4 (xeno); NbExp=5; IntAct=EBI-978348, EBI-978341;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Chylomicrons in the plasma.
CC -!- SIMILARITY: Contains 8 Sushi (CCP/SCR) domains.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-17 is the initiator.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M31452; AAA36507.1; -; mRNA.
DR EMBL; M62486; AAA36506.1; -; Genomic_DNA.
DR EMBL; M62475; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62476; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62477; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62478; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62479; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62480; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62481; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62482; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62484; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; M62485; AAA36506.1; JOINED; Genomic_DNA.
DR EMBL; BC022312; AAH22312.1; -; mRNA.
DR EMBL; X07853; CAA30701.1; -; mRNA.
DR EMBL; X04284; CAB51244.1; -; Genomic_DNA.
DR EMBL; X04296; CAA27839.1; -; Genomic_DNA.
DR EMBL; X02865; CAA26617.1; -; mRNA.
DR PIR; A33568; NBHUC4.
DR RefSeq; NP_000706.1; NM_000715.3.
DR RefSeq; XP_005273308.1; XM_005273251.1.
DR RefSeq; XP_005273309.1; XM_005273252.1.
DR UniGene; Hs.1012; -.
DR PDB; 2A55; NMR; -; A=49-172.
DR PDB; 4B0F; X-ray; 2.80 A; A/B/C/D/E/F/G=540-597.
DR PDBsum; 2A55; -.
DR PDBsum; 4B0F; -.
DR ProteinModelPortal; P04003; -.
DR SMR; P04003; 49-597.
DR IntAct; P04003; 6.
DR STRING; 9606.ENSP00000356037; -.
DR PhosphoSite; P04003; -.
DR DMDM; 416733; -.
DR PaxDb; P04003; -.
DR PeptideAtlas; P04003; -.
DR PRIDE; P04003; -.
DR DNASU; 722; -.
DR Ensembl; ENST00000367070; ENSP00000356037; ENSG00000123838.
DR GeneID; 722; -.
DR KEGG; hsa:722; -.
DR UCSC; uc001hfo.3; human.
DR CTD; 722; -.
DR GeneCards; GC01P207277; -.
DR HGNC; HGNC:1325; C4BPA.
DR HPA; HPA000926; -.
DR HPA; HPA001578; -.
DR MIM; 120830; gene.
DR neXtProt; NX_P04003; -.
DR PharmGKB; PA25905; -.
DR eggNOG; NOG150577; -.
DR HOGENOM; HOG000015324; -.
DR HOVERGEN; HBG004657; -.
DR InParanoid; P04003; -.
DR KO; K04002; -.
DR OMA; VENETIG; -.
DR OrthoDB; EOG725DH2; -.
DR PhylomeDB; P04003; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P04003; -.
DR GenomeRNAi; 722; -.
DR NextBio; 2938; -.
DR PRO; PR:P04003; -.
DR ArrayExpress; P04003; -.
DR Bgee; P04003; -.
DR CleanEx; HS_C4BPA; -.
DR Genevestigator; P04003; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR InterPro; IPR000436; Sushi_SCR_CCP.
DR Pfam; PF00084; Sushi; 8.
DR SMART; SM00032; CCP; 8.
DR SUPFAM; SSF57535; SSF57535; 8.
DR PROSITE; PS50923; SUSHI; 8.
PE 1: Evidence at protein level;
KW 3D-structure; Complement pathway; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity;
KW Innate immunity; Polymorphism; Reference proteome; Repeat; Secreted;
KW Signal; Sushi.
FT SIGNAL 1 48
FT CHAIN 49 597 C4b-binding protein alpha chain.
FT /FTId=PRO_0000005888.
FT DOMAIN 49 110 Sushi 1.
FT DOMAIN 111 172 Sushi 2.
FT DOMAIN 173 236 Sushi 3.
FT DOMAIN 237 296 Sushi 4.
FT DOMAIN 297 362 Sushi 5.
FT DOMAIN 363 424 Sushi 6.
FT DOMAIN 425 482 Sushi 7.
FT DOMAIN 483 540 Sushi 8.
FT CARBOHYD 221 221 N-linked (GlcNAc...).
FT CARBOHYD 506 506 N-linked (GlcNAc...).
FT CARBOHYD 528 528 N-linked (GlcNAc...).
FT DISULFID 50 96 By similarity.
FT DISULFID 81 108 By similarity.
FT DISULFID 113 154 By similarity.
FT DISULFID 140 170 By similarity.
FT DISULFID 175 217 By similarity.
FT DISULFID 203 234 By similarity.
FT DISULFID 239 281 By similarity.
FT DISULFID 267 294 By similarity.
FT DISULFID 299 348 By similarity.
FT DISULFID 332 360 By similarity.
FT DISULFID 365 409 By similarity.
FT DISULFID 399 422 By similarity.
FT DISULFID 426 468 By similarity.
FT DISULFID 454 480 By similarity.
FT DISULFID 484 525 By similarity.
FT DISULFID 511 538 By similarity.
FT DISULFID 546 546 Interchain (with beta chain) (Potential).
FT DISULFID 558 558 Interchain (with beta chain) (Potential).
FT VARIANT 4 4 P -> Q (in dbSNP:rs55867570).
FT /FTId=VAR_061123.
FT VARIANT 60 60 A -> V (in dbSNP:rs17020956).
FT /FTId=VAR_048815.
FT VARIANT 240 240 R -> H (in dbSNP:rs45574833).
FT /FTId=VAR_061124.
FT VARIANT 300 300 I -> T (in dbSNP:rs4844573).
FT /FTId=VAR_024420.
FT VARIANT 357 357 Y -> H.
FT /FTId=VAR_001978.
FT VARIANT 473 473 W -> L (in dbSNP:rs1801341).
FT /FTId=VAR_012038.
FT STRAND 85 87
FT STRAND 98 103
FT STRAND 108 110
FT STRAND 131 133
FT STRAND 158 160
FT HELIX 547 555
FT STRAND 558 561
FT HELIX 562 589
FT HELIX 591 596
SQ SEQUENCE 597 AA; 67033 MW; 67E03F2EA85A16DD CRC64;
MHPPKTPSGA LHRKRKMAAW PFSRLWKVSD PILFQMTLIA ALLPAVLGNC GPPPTLSFAA
PMDITLTETR FKTGTTLKYT CLPGYVRSHS TQTLTCNSDG EWVYNTFCIY KRCRHPGELR
NGQVEIKTDL SFGSQIEFSC SEGFFLIGST TSRCEVQDRG VGWSHPLPQC EIVKCKPPPD
IRNGRHSGEE NFYAYGFSVT YSCDPRFSLL GHASISCTVE NETIGVWRPS PPTCEKITCR
KPDVSHGEMV SGFGPIYNYK DTIVFKCQKG FVLRGSSVIH CDADSKWNPS PPACEPNSCI
NLPDIPHASW ETYPRPTKED VYVVGTVLRY RCHPGYKPTT DEPTTVICQK NLRWTPYQGC
EALCCPEPKL NNGEITQHRK SRPANHCVYF YGDEISFSCH ETSRFSAICQ GDGTWSPRTP
SCGDICNFPP KIAHGHYKQS SSYSFFKEEI IYECDKGYIL VGQAKLSCSY SHWSAPAPQC
KALCRKPELV NGRLSVDKDQ YVEPENVTIQ CDSGYGVVGP QSITCSGNRT WYPEVPKCEW
ETPEGCEQVL TGKRLMQCLP NPEDVKMALE VYKLSLEIEQ LELQRDSARQ STLDKEL
//
MIM
120830
*RECORD*
*FIELD* NO
120830
*FIELD* TI
*120830 COMPLEMENT COMPONENT 4-BINDING PROTEIN, ALPHA; C4BPA
;;C4b RECEPTOR; C4BP
COMPLEMENT COMPONENT 4-BINDING PROTEIN, ALPHA-LIKE 1, INCLUDED; C4BPAL1,
read moreINCLUDED
*FIELD* TX
DESCRIPTION
C4b (120820)-binding protein is involved in regulation of the complement
system. It is a multimeric protein comprising 7 identical alpha chains,
encoded by C4BPA, and a single beta chain, encoded by C4BPB (120831).
The alpha and beta chains have molecular masses of 70 and 45 kD,
respectively. Both subunits belong to a superfamily of proteins composed
predominantly of tandemly arranged short consensus repeats (SCR) of
approximately 60 amino acids in length (Aso et al., 1991).
CLONING
By isoelectric focusing under completely denaturing conditions,
Rodriguez de Cordoba et al. (1983, 1984) identified 2 allelic variants
of C4BP.
Matsuguchi et al. (1989) showed that proline-rich protein (PRP), a
glycoprotein present in chylomicrons, is identical to C4BP.
GENE FUNCTION
C4BP of man has been studied by Gigli et al. (1979) and Nagasawa and
Stroud (1980). Gigli et al. (1979) showed that C4BP is an essential
cofactor for C3b inactivator (CFI; 217030) in the proteolytic cleavage
of C4b and, to a lesser extent, of C3b (120700), and functions as the
regulator of C3 convertase of the classical pathway. Kaidoh et al.
(1981) stated that the C3 convertase of the classical pathway consists
of C2 (613927) and C4; that of the alternative pathway of factor B (CFB;
138470) and C3 (120700). Each C3 convertase plays a key role in the
amplification process of complement activation.
Brodeur et al. (2003) identified a 23-kD protein that bound CD40
(109535) as C4BP-alpha. Flow cytometric analysis demonstrated binding of
C4BP to human B-cell lines expressing CD40, but not to cells from
CD40-deficient patients. Competitive binding analysis showed that CD40LG
(300386) and C4BP bound distinct sites on CD40. C4BP induced
proliferation, upregulation of CD54 (ICAM1; 147840) and CD86 (601020)
surface expression, and, together with IL4 (147780), IgE synthesis in
normal B cells, but not in B cells from patients with CD40 or IKBKG
(300248) deficiencies. Immunohistochemical analysis showed that C4BP
colocalized with CD40 on B cells in tonsillar germinal centers. Brodeur
et al. (2003) proposed that C4BP is an activating ligand for CD40 and
represents an interface between complement and B-cell activation.
Strains of Neisseria gonorrhoeae use their outer membrane porin (Por)
molecules to bind C4BP and resist killing by human, but not rodent,
rabbit, and nonhuman primate, serum complement. The lack of
susceptibility to N. gonorrhoeae infection in nonhuman species prevents
the development of an animal model to study the infection in vivo.
Ngampasutadol et al. (2005) found that gonococci expressing Por1B, but
not Por1A, were resistant to killing by chimpanzee serum. Addition of
human C4BP to animal sera rescued N. gonorrhoeae from killing. Nonhuman
C4bp did not bind N. gonorrhoeae. Comparative sequence analysis
suggested 4 potential residues in human C4BP that may be critical for
its interaction with Por1A. Ngampasutadol et al. (2005) concluded that
C4BP sequence differences account for the restriction of serum
resistance of N. gonorrhoeae to humans and, in some instances,
chimpanzees.
GENE STRUCTURE
Aso et al. (1991) found that the C4BPA gene comprises 12 exons and spans
about 40 kb. Each of the 8 SCRs that constitute the N-terminal 491
residues is encoded by a single exon, except for the second, which is
encoded by 2 separate exons.
MAPPING
Rodriguez de Cordoba et al. (1984) studied 3 pedigrees informative for
segregation of C4BP and C3b receptor (C3BR, or CR1; 120620). Neither
C4BP nor C3BR is closely linked to HLA (Rodriguez de Cordoba et al.,
1983; Hatch et al., 1984); however, segregation in the 3 kindreds
indicated that the 2 loci are closely linked in man. There were 10
informative meioses with no recombinants--maximum lod score = 2.4 at
theta 0.0. The cosegregation of 2 common alleles supported close linkage
by the principle of linkage disequilibrium. These 2 closely linked genes
determine functionally related proteins. Rodriguez de Cordoba et al.
(1985) concluded that HF (CFH; 134370), C4BP, C3BR, and C3DR (CR2;
120650) represent a cluster of linked genes encoding complement
components regulating the activation of C3. They called the cluster RCA
for regulators of complement activation. They showed, furthermore, that
the RCA cluster segregates independently of HLA, the C2, CFB, C4 cluster
(on 6p), and C3 (on 19p). Using pulsed-field gel electrophoresis,
Rey-Campos et al. (1988) showed that the RCA cluster is physically
linked and aligned as CR1--CR2--DAF (CD55; 125240)--C4BP in an 800-kb
DNA segment. The very tight linkage between CR1 and C4BP revealed by
family linkage studies contrasts with the relatively long DNA distance
between these genes, suggesting that there may be mechanisms interfering
with recombination within the RCA gene cluster. The probe for HF did not
hybridize to any of the fragments recognized by the CR1, CR2, DAF, or
C4BP probes. Rey-Campos et al. (1988) estimated that the RCA cluster may
exceed 1 Mb in length and, given the recombination data, may be as long
as 7 Mb. By Southern analysis of hybrid cell DNA, Hing et al. (1988)
assigned C4BP and HF to 1q.
Kaidoh et al. (1981) showed that mouse C4bp is polymorphic and is
determined by a gene in the major histocompatibility complex. However,
Barnum et al. (1989) assigned the mouse gene to chromosome 1.
- PSEUDOGENES
Sanchez-Corral et al. (1993) identified a gene, symbolized C4BPAL1 by
them, as a member of the human RCA gene cluster that arose from
duplication of the C4BPA gene. It is in the same 5-prime to 3-prime
orientation found in all RCA genes. C4BPAL1 includes 9 exon-like regions
homologous to several exons of the C4BPA gene. Analysis of its sequence
suggested that it is currently a pseudogene in humans. However,
comparisons between C4BPAL1 and the human and murine C4BPA genes showed
sequence conservation which strongly suggested that, for a long period
of time, the gene was functional.
MOLECULAR GENETICS
Blom et al. (2008) identified an arg240-to-his (R240H) SNP in the C4BPA
gene that was associated with atypical hemolytic uremic syndrome (aHUS;
235400). The heterozygous change was found in 6 of 166 patients with
aHUS and in 5 of 542 healthy controls. Three of the 6 patients with this
SNP carried mutations in other known aHUS susceptibility genes,
including MCP (120920) and CFH (134370). The findings were replicated in
another sample. Functional expression studies showed that the C4BPA
variant had impaired ability to bind C3b and act as a cofactor in its
degradation. The findings supported the hypothesis that dysregulation of
the alternative complement pathway can lead to aHUS.
*FIELD* SA
Andersson et al. (1990); Rodriguez de Cordoba et al. (1984)
*FIELD* RF
1. Andersson, A.; Dahlback, B.; Hanson, C.; Hillarp, A.; Levan, G.;
Szpirer, J.; Szpirer, C.: Genes for C4b-binding protein alpha- and
beta-chains (C4BPA and C4BPB) are located on chromosome 1, band 1q32,
in humans and on chromosome 13 in rats. Somat. Cell Molec. Genet. 16:
493-500, 1990.
2. Aso, T.; Okamura, S.; Matsuguchi, T.; Sakamoto, N.; Sata, T.; Niho,
Y.: Genomic organization of the alpha chain of the human C4b-binding
protein gene. Biochem. Biophys. Res. Commun. 174: 222-227, 1991.
3. Barnum, S. R.; Kristensen, T.; Chaplin, D. D.; Seldin, M. F.; Tack,
B. F.: Molecular analysis of the murine C4b-binding protein gene:
chromosome assignment and partial gene organization. Biochemistry 28:
8312-8317, 1989.
4. Blom, A. M.; Bergstrom, F.; Edey, M.; Diaz-Torres, M.; Kavanagh,
D.; Lampe, A.; Goodship, J. A.; Strain, L.; Moghal, N.; McHugh, M.;
Inward, C.; Tomson, C.; Fremeaux-Bacchi, V.; Villoutreix, B. O.; Goodship,
T. H. J.: A novel non-synonymous polymorphism (p.arg240his) in C4b-binding
protein is associated with atypical hemolytic uremic syndrome and
leads to impaired alternative pathway cofactor activity. J. Immun. 180:
6385-6391, 2008.
5. Brodeur, S. R.; Angelini, F.; Bacharier, L. B.; Blom, A. M.; Mizoguchi,
E.; Fujiwara, H.; Plebani, A.; Notarangelo, L. D.; Dahlback, B.; Tsitsikov,
E.; Geha, R. S.: C4b-binding protein (C4BP) activates B cells through
the CD40 receptor. Immunity 18: 837-848, 2003.
6. Gigli, I.; Fujita, T.; Nussenzweig, V.: Modulation of the classical
pathway C3 convertase by plasma proteins C4 binding protein and C3b
inactivator. Proc. Nat. Acad. Sci. 76: 6596-6600, 1979.
7. Hatch, J. A.; Atkinson, J. P.; Suarez, B. K.; Dykman, T. R.: Evaluation
of linkage of the human C3b/C4b receptor to HLA. J. Immun. 132:
2168-2169, 1984.
8. Hing, S.; Day, A. J.; Linton, S. J.; Ripoche, J.; Sim, R. B.; Reid,
K. B. M.; Solomon, E.: Assignment of complement components C4 binding
protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA
probes. Ann. Hum. Genet. 52: 117-122, 1988.
9. Kaidoh, T.; Natsuume-Sakai, S.; Takahashi, M.: Murine binding
protein of the fourth component of complement: structural polymorphism
and its linkage to the major histocompatibility complex. Proc. Nat.
Acad. Sci. 78: 3794-3798, 1981.
10. Matsuguchi, T.; Okamura, S.; Aso, T.; Sata, T.; Niho, Y.: Molecular
cloning of the cDNA coding for proline-rich protein (PRP): identity
of PRP as C4b-binding protein. Biochem. Biophys. Res. Commun. 165:
138-144, 1989.
11. Nagasawa, S.; Stroud, R. M.: Purification and characterization
of a macromolecular weight cofactor for C3b-inactivator, C4bC3bINA-cofactor,
of human plasma. Molec. Immun. 17: 1365-1372, 1980.
12. Ngampasutadol, J.; Ram, S.; Blom, A. M.; Jarva, H.; Jerse, A.
E.; Lien, E.; Goguen, J.; Gulati, S.; Rice, P. A.: Human C4b-binding
protein selectively interacts with Neisseria gonorrhoeae and results
in species-specific infection. Proc. Nat. Acad. Sci. 102: 17142-17147,
2005.
13. Rey-Campos, J.; Rubinstein, P.; Rodriguez de Cordoba, S.: A physical
map of the human regulator of complement activation gene cluster linking
the complement genes CR1, CR2, DAF, and C4BP. J. Exp. Med. 167:
664-669, 1988.
14. Rodriguez de Cordoba, S.; Dykman, T. R.; Ginsberg-Fellner, F.;
Ercilla, G.; Aqua, M.; Atkinson, J. P.; Rubinstein, P.: Evidence
for linkage between the loci coding for the binding protein for the
fourth component of human complement (C4BP) and for the C3b/C4b receptor. Proc.
Nat. Acad. Sci. 81: 7890-7892, 1984.
15. Rodriguez de Cordoba, S.; Ferreira, A.; Nussenzweig, V.; Rubinstein,
P.: Genetic polymorphism of human C4-binding protein. J. Immun. 131:
1565-1569, 1983.
16. Rodriguez de Cordoba, S.; Lublin, D. M.; Rubinstein, P.; Atkinson,
J. P.: Human genes for three complement components that regulate
the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195,
1985.
17. Rodriguez de Cordoba, S.; Rubinstein, P.; Ferreira, A.: High
resolution isoelectric focusing of immunoprecipitated proteins under
denaturing conditions: a simple analytical method applied to the study
of complement component polymorphisms. J. Immun. Methods 69: 165-172,
1984.
18. Sanchez-Corral, P.; Pardo-Manuel de Villena, F.; Rey-Campos, J.;
Rodriguez de Cordoba, S.: C4BPAL1, a member of the human regulator
of complement activation (RCA) gene cluster that resulted from the
duplication of the gene coding for the alpha-chain of C4b-binding
protein. Genomics 17: 185-193, 1993.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/4/2009
Paul J. Converse - updated: 3/2/2007
Paul J. Converse - updated: 5/2/2006
Victor A. McKusick - edited: 6/24/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 08/07/2013
carol: 4/25/2011
ckniffin: 8/4/2009
carol: 5/4/2007
mgross: 3/12/2007
terry: 3/2/2007
mgross: 5/10/2006
terry: 5/2/2006
terry: 10/18/2000
dkim: 7/21/1998
dkim: 6/30/1998
mark: 6/24/1997
mark: 2/21/1997
supermim: 3/16/1992
carol: 3/2/1992
carol: 3/1/1991
carol: 2/25/1991
carol: 1/2/1991
supermim: 3/20/1990
*RECORD*
*FIELD* NO
120830
*FIELD* TI
*120830 COMPLEMENT COMPONENT 4-BINDING PROTEIN, ALPHA; C4BPA
;;C4b RECEPTOR; C4BP
COMPLEMENT COMPONENT 4-BINDING PROTEIN, ALPHA-LIKE 1, INCLUDED; C4BPAL1,
read moreINCLUDED
*FIELD* TX
DESCRIPTION
C4b (120820)-binding protein is involved in regulation of the complement
system. It is a multimeric protein comprising 7 identical alpha chains,
encoded by C4BPA, and a single beta chain, encoded by C4BPB (120831).
The alpha and beta chains have molecular masses of 70 and 45 kD,
respectively. Both subunits belong to a superfamily of proteins composed
predominantly of tandemly arranged short consensus repeats (SCR) of
approximately 60 amino acids in length (Aso et al., 1991).
CLONING
By isoelectric focusing under completely denaturing conditions,
Rodriguez de Cordoba et al. (1983, 1984) identified 2 allelic variants
of C4BP.
Matsuguchi et al. (1989) showed that proline-rich protein (PRP), a
glycoprotein present in chylomicrons, is identical to C4BP.
GENE FUNCTION
C4BP of man has been studied by Gigli et al. (1979) and Nagasawa and
Stroud (1980). Gigli et al. (1979) showed that C4BP is an essential
cofactor for C3b inactivator (CFI; 217030) in the proteolytic cleavage
of C4b and, to a lesser extent, of C3b (120700), and functions as the
regulator of C3 convertase of the classical pathway. Kaidoh et al.
(1981) stated that the C3 convertase of the classical pathway consists
of C2 (613927) and C4; that of the alternative pathway of factor B (CFB;
138470) and C3 (120700). Each C3 convertase plays a key role in the
amplification process of complement activation.
Brodeur et al. (2003) identified a 23-kD protein that bound CD40
(109535) as C4BP-alpha. Flow cytometric analysis demonstrated binding of
C4BP to human B-cell lines expressing CD40, but not to cells from
CD40-deficient patients. Competitive binding analysis showed that CD40LG
(300386) and C4BP bound distinct sites on CD40. C4BP induced
proliferation, upregulation of CD54 (ICAM1; 147840) and CD86 (601020)
surface expression, and, together with IL4 (147780), IgE synthesis in
normal B cells, but not in B cells from patients with CD40 or IKBKG
(300248) deficiencies. Immunohistochemical analysis showed that C4BP
colocalized with CD40 on B cells in tonsillar germinal centers. Brodeur
et al. (2003) proposed that C4BP is an activating ligand for CD40 and
represents an interface between complement and B-cell activation.
Strains of Neisseria gonorrhoeae use their outer membrane porin (Por)
molecules to bind C4BP and resist killing by human, but not rodent,
rabbit, and nonhuman primate, serum complement. The lack of
susceptibility to N. gonorrhoeae infection in nonhuman species prevents
the development of an animal model to study the infection in vivo.
Ngampasutadol et al. (2005) found that gonococci expressing Por1B, but
not Por1A, were resistant to killing by chimpanzee serum. Addition of
human C4BP to animal sera rescued N. gonorrhoeae from killing. Nonhuman
C4bp did not bind N. gonorrhoeae. Comparative sequence analysis
suggested 4 potential residues in human C4BP that may be critical for
its interaction with Por1A. Ngampasutadol et al. (2005) concluded that
C4BP sequence differences account for the restriction of serum
resistance of N. gonorrhoeae to humans and, in some instances,
chimpanzees.
GENE STRUCTURE
Aso et al. (1991) found that the C4BPA gene comprises 12 exons and spans
about 40 kb. Each of the 8 SCRs that constitute the N-terminal 491
residues is encoded by a single exon, except for the second, which is
encoded by 2 separate exons.
MAPPING
Rodriguez de Cordoba et al. (1984) studied 3 pedigrees informative for
segregation of C4BP and C3b receptor (C3BR, or CR1; 120620). Neither
C4BP nor C3BR is closely linked to HLA (Rodriguez de Cordoba et al.,
1983; Hatch et al., 1984); however, segregation in the 3 kindreds
indicated that the 2 loci are closely linked in man. There were 10
informative meioses with no recombinants--maximum lod score = 2.4 at
theta 0.0. The cosegregation of 2 common alleles supported close linkage
by the principle of linkage disequilibrium. These 2 closely linked genes
determine functionally related proteins. Rodriguez de Cordoba et al.
(1985) concluded that HF (CFH; 134370), C4BP, C3BR, and C3DR (CR2;
120650) represent a cluster of linked genes encoding complement
components regulating the activation of C3. They called the cluster RCA
for regulators of complement activation. They showed, furthermore, that
the RCA cluster segregates independently of HLA, the C2, CFB, C4 cluster
(on 6p), and C3 (on 19p). Using pulsed-field gel electrophoresis,
Rey-Campos et al. (1988) showed that the RCA cluster is physically
linked and aligned as CR1--CR2--DAF (CD55; 125240)--C4BP in an 800-kb
DNA segment. The very tight linkage between CR1 and C4BP revealed by
family linkage studies contrasts with the relatively long DNA distance
between these genes, suggesting that there may be mechanisms interfering
with recombination within the RCA gene cluster. The probe for HF did not
hybridize to any of the fragments recognized by the CR1, CR2, DAF, or
C4BP probes. Rey-Campos et al. (1988) estimated that the RCA cluster may
exceed 1 Mb in length and, given the recombination data, may be as long
as 7 Mb. By Southern analysis of hybrid cell DNA, Hing et al. (1988)
assigned C4BP and HF to 1q.
Kaidoh et al. (1981) showed that mouse C4bp is polymorphic and is
determined by a gene in the major histocompatibility complex. However,
Barnum et al. (1989) assigned the mouse gene to chromosome 1.
- PSEUDOGENES
Sanchez-Corral et al. (1993) identified a gene, symbolized C4BPAL1 by
them, as a member of the human RCA gene cluster that arose from
duplication of the C4BPA gene. It is in the same 5-prime to 3-prime
orientation found in all RCA genes. C4BPAL1 includes 9 exon-like regions
homologous to several exons of the C4BPA gene. Analysis of its sequence
suggested that it is currently a pseudogene in humans. However,
comparisons between C4BPAL1 and the human and murine C4BPA genes showed
sequence conservation which strongly suggested that, for a long period
of time, the gene was functional.
MOLECULAR GENETICS
Blom et al. (2008) identified an arg240-to-his (R240H) SNP in the C4BPA
gene that was associated with atypical hemolytic uremic syndrome (aHUS;
235400). The heterozygous change was found in 6 of 166 patients with
aHUS and in 5 of 542 healthy controls. Three of the 6 patients with this
SNP carried mutations in other known aHUS susceptibility genes,
including MCP (120920) and CFH (134370). The findings were replicated in
another sample. Functional expression studies showed that the C4BPA
variant had impaired ability to bind C3b and act as a cofactor in its
degradation. The findings supported the hypothesis that dysregulation of
the alternative complement pathway can lead to aHUS.
*FIELD* SA
Andersson et al. (1990); Rodriguez de Cordoba et al. (1984)
*FIELD* RF
1. Andersson, A.; Dahlback, B.; Hanson, C.; Hillarp, A.; Levan, G.;
Szpirer, J.; Szpirer, C.: Genes for C4b-binding protein alpha- and
beta-chains (C4BPA and C4BPB) are located on chromosome 1, band 1q32,
in humans and on chromosome 13 in rats. Somat. Cell Molec. Genet. 16:
493-500, 1990.
2. Aso, T.; Okamura, S.; Matsuguchi, T.; Sakamoto, N.; Sata, T.; Niho,
Y.: Genomic organization of the alpha chain of the human C4b-binding
protein gene. Biochem. Biophys. Res. Commun. 174: 222-227, 1991.
3. Barnum, S. R.; Kristensen, T.; Chaplin, D. D.; Seldin, M. F.; Tack,
B. F.: Molecular analysis of the murine C4b-binding protein gene:
chromosome assignment and partial gene organization. Biochemistry 28:
8312-8317, 1989.
4. Blom, A. M.; Bergstrom, F.; Edey, M.; Diaz-Torres, M.; Kavanagh,
D.; Lampe, A.; Goodship, J. A.; Strain, L.; Moghal, N.; McHugh, M.;
Inward, C.; Tomson, C.; Fremeaux-Bacchi, V.; Villoutreix, B. O.; Goodship,
T. H. J.: A novel non-synonymous polymorphism (p.arg240his) in C4b-binding
protein is associated with atypical hemolytic uremic syndrome and
leads to impaired alternative pathway cofactor activity. J. Immun. 180:
6385-6391, 2008.
5. Brodeur, S. R.; Angelini, F.; Bacharier, L. B.; Blom, A. M.; Mizoguchi,
E.; Fujiwara, H.; Plebani, A.; Notarangelo, L. D.; Dahlback, B.; Tsitsikov,
E.; Geha, R. S.: C4b-binding protein (C4BP) activates B cells through
the CD40 receptor. Immunity 18: 837-848, 2003.
6. Gigli, I.; Fujita, T.; Nussenzweig, V.: Modulation of the classical
pathway C3 convertase by plasma proteins C4 binding protein and C3b
inactivator. Proc. Nat. Acad. Sci. 76: 6596-6600, 1979.
7. Hatch, J. A.; Atkinson, J. P.; Suarez, B. K.; Dykman, T. R.: Evaluation
of linkage of the human C3b/C4b receptor to HLA. J. Immun. 132:
2168-2169, 1984.
8. Hing, S.; Day, A. J.; Linton, S. J.; Ripoche, J.; Sim, R. B.; Reid,
K. B. M.; Solomon, E.: Assignment of complement components C4 binding
protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA
probes. Ann. Hum. Genet. 52: 117-122, 1988.
9. Kaidoh, T.; Natsuume-Sakai, S.; Takahashi, M.: Murine binding
protein of the fourth component of complement: structural polymorphism
and its linkage to the major histocompatibility complex. Proc. Nat.
Acad. Sci. 78: 3794-3798, 1981.
10. Matsuguchi, T.; Okamura, S.; Aso, T.; Sata, T.; Niho, Y.: Molecular
cloning of the cDNA coding for proline-rich protein (PRP): identity
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*FIELD* CN
Cassandra L. Kniffin - updated: 8/4/2009
Paul J. Converse - updated: 3/2/2007
Paul J. Converse - updated: 5/2/2006
Victor A. McKusick - edited: 6/24/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 08/07/2013
carol: 4/25/2011
ckniffin: 8/4/2009
carol: 5/4/2007
mgross: 3/12/2007
terry: 3/2/2007
mgross: 5/10/2006
terry: 5/2/2006
terry: 10/18/2000
dkim: 7/21/1998
dkim: 6/30/1998
mark: 6/24/1997
mark: 2/21/1997
supermim: 3/16/1992
carol: 3/2/1992
carol: 3/1/1991
carol: 2/25/1991
carol: 1/2/1991
supermim: 3/20/1990