Full text data of APOH
APOH
(B2G1)
[Confidence: low (only semi-automatic identification from reviews)]
Beta-2-glycoprotein 1 (APC inhibitor; Activated protein C-binding protein; Anticardiolipin cofactor; Apolipoprotein H; Apo-H; Beta-2-glycoprotein I; B2GPI; Beta(2)GPI; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Beta-2-glycoprotein 1 (APC inhibitor; Activated protein C-binding protein; Anticardiolipin cofactor; Apolipoprotein H; Apo-H; Beta-2-glycoprotein I; B2GPI; Beta(2)GPI; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P02749
ID APOH_HUMAN Reviewed; 345 AA.
AC P02749; B2R9M3; Q9UCN7;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 3.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Beta-2-glycoprotein 1;
DE AltName: Full=APC inhibitor;
DE AltName: Full=Activated protein C-binding protein;
DE AltName: Full=Anticardiolipin cofactor;
DE AltName: Full=Apolipoprotein H;
DE Short=Apo-H;
DE AltName: Full=Beta-2-glycoprotein I;
DE Short=B2GPI;
DE Short=Beta(2)GPI;
DE Flags: Precursor;
GN Name=APOH; Synonyms=B2G1;
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=1650181;
RA Steinkasserer A., Estaller C., Weiss E., Sim R.B., Day A.J.;
RT "Complete nucleotide and deduced amino acid sequence of human beta 2-
RT glycoprotein I.";
RL Biochem. J. 277:387-391(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1655523; DOI=10.1016/0014-5793(91)81065-G;
RA Kristensen T., Schousboe I., Boel E., Mulvihill E.M., Hansen R.R.,
RA Moeller K.B., Moeller N.P.H., Sottrup-Jensen L.;
RT "Molecular cloning and mammalian expression of human beta 2-
RT glycoprotein I cDNA.";
RL FEBS Lett. 289:183-186(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1748314; DOI=10.1016/0378-1119(91)90449-L;
RA Mehdi H., Nunn M., Steel D.M., Whitehead A.S., Perez M., Walker L.,
RA Peeples M.E.;
RT "Nucleotide sequence and expression of the human gene encoding
RT apolipoprotein H (beta 2-glycoprotein I).";
RL Gene 108:293-298(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1339416; DOI=10.1007/BF02591656;
RA Day J.R., O'Hara P.J., Grant F.J., Lofton-Day C.E., Berkaw M.N.,
RA Werner P., Arnaud P.;
RT "Molecular cloning and sequence analysis of the cDNA encoding human
RT apolipoprotein H (beta 2-glycoprotein I).";
RL Int. J. Clin. Lab. Res. 21:256-263(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1777418; DOI=10.1093/intimm/3.12.1217;
RA Matsuura E., Igarashi M., Igarashi Y., Nagae H., Ichikawa K.,
RA Yasuda T., Koike T.;
RT "Molecular definition of human beta 2-glycoprotein I (beta 2-GPI) by
RT cDNA cloning and inter-species differences of beta 2-GPI in
RT alternation of anticardiolipin binding.";
RL Int. Immunol. 3:1217-1221(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9914524; DOI=10.1046/j.1432-1327.1999.00063.x;
RA Okkels H., Rasmussen T.E., Sanghera D.K., Kamboh M.I., Kristensen T.;
RT "Structure of the human beta2-glycoprotein I (apolipoprotein H)
RT gene.";
RL Eur. J. Biochem. 259:435-440(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-107.
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASN-107; HIS-154;
RP LEU-266 AND SER-335.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [10]
RP PROTEIN SEQUENCE OF 20-345, GLYCOSYLATION AT ASN-162; ASN-183; ASN-193
RP AND ASN-253, AND DISULFIDE BONDS.
RX PubMed=6587378; DOI=10.1073/pnas.81.12.3640;
RA Lozier J., Takahashi N., Putnam F.W.;
RT "Complete amino acid sequence of human plasma beta 2-glycoprotein I.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:3640-3644(1984).
RN [11]
RP PROTEIN SEQUENCE OF 20-44.
RX PubMed=1602135;
RA Matsuura E., Igarashi Y., Fujimoto M., Ichikawa K., Suzuki T.,
RA Sumida T., Yasuda T., Koike T.;
RT "Heterogeneity of anticardiolipin antibodies defined by the
RT anticardiolipin cofactor.";
RL J. Immunol. 148:3885-3891(1992).
RN [12]
RP PROTEIN SEQUENCE OF 20-43.
RX PubMed=2349221; DOI=10.1073/pnas.87.11.4120;
RA McNeil H.P., Simpson R.J., Chesterman C.N., Krilis S.A.;
RT "Anti-phospholipid antibodies are directed against a complex antigen
RT that includes a lipid-binding inhibitor of coagulation: beta 2-
RT glycoprotein I (apolipoprotein H).";
RL Proc. Natl. Acad. Sci. U.S.A. 87:4120-4124(1990).
RN [13]
RP PROTEIN SEQUENCE OF 20-38.
RC TISSUE=Ovarian follicular fluid;
RX PubMed=11250549; DOI=10.1016/S1096-4959(00)00359-6;
RA Aleporou-Marinou V., Pappa H., Yalouris P., Patargias T.;
RT "Purification of apolipoprotein H (beta 2-glycoprotein I)-like protein
RT from human follicular fluid.";
RL Comp. Biochem. Physiol. 128B:537-542(2001).
RN [14]
RP DISULFIDE BONDS IN C-TERMINAL DOMAIN.
RX PubMed=1426288; DOI=10.1016/0014-5793(92)81442-O;
RA Steinkkasserer A., Barlow P.N., Willis A.C., Kertesz Z.,
RA Campbell I.D., Sim R.B., Norman D.G.;
RT "Activity, disulphide mapping and structural modelling of the fifth
RT domain of human beta 2-glycoprotein I.";
RL FEBS Lett. 313:193-197(1992).
RN [15]
RP STRUCTURE OF CARBOHYDRATES.
RX PubMed=9155091; DOI=10.1023/A:1026378825391;
RA Gambino R., Ruiu G., Pagano G., Cassader M.;
RT "Qualitative analysis of the carbohydrate composition of
RT apolipoprotein H.";
RL J. Protein Chem. 16:205-212(1997).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162 AND ASN-253, AND MASS
RP SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162; ASN-183 AND ASN-193,
RP AND MASS 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 [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162; ASN-183; ASN-193 AND
RP ASN-253, AND MASS 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 [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162 AND ASN-253, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162; ASN-183; ASN-193 AND
RP ASN-253, AND MASS 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 [21]
RP GLYCOSYLATION AT ASN-162.
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.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
RC TISSUE=Plasma;
RX PubMed=10508150; DOI=10.1093/emboj/18.19.5166;
RA Bouma B., de Groot P.G., van Den Elsen J.M.H., Ravelli R.B.G.,
RA Schouten A., Simmelink M.J.A., Derksen R.H.W.M., Kroon J., Gros P.;
RT "Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids
RT based on its crystal structure.";
RL EMBO J. 18:5166-5174(1999).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.87 ANGSTROMS).
RX PubMed=10562535; DOI=10.1093/emboj/18.22.6228;
RA Schwarzenbacher R., Zeth K., Diederichs K., Gries A., Kostner G.M.,
RA Laggner P., Prassl R.;
RT "Crystal structure of human beta2-glycoprotein I: implications for
RT phospholipid binding and the antiphospholipid syndrome.";
RL EMBO J. 18:6228-6239(1999).
RN [26]
RP VARIANT LEU-266.
RX PubMed=8099061; DOI=10.1007/BF00217367;
RA Steinkasserer A., Doerner C., Wuerzner R., Sim R.B.;
RT "Human beta 2-glycoprotein I: molecular analysis of DNA and amino acid
RT polymorphism.";
RL Hum. Genet. 91:401-402(1993).
RN [27]
RP VARIANT ASN-107.
RX PubMed=9225969; DOI=10.1007/s004390050465;
RA Sanghera D.K., Kristensen T., Hamman R.F., Kamboh M.I.;
RT "Molecular basis of the apolipoprotein H (beta 2-glycoprotein I)
RT protein polymorphism.";
RL Hum. Genet. 100:57-62(1997).
RN [28]
RP VARIANTS GLY-325 AND SER-335.
RX PubMed=9063752; DOI=10.1093/hmg/6.2.311;
RA Sanghera D.K., Wagenknecht D.R., McIntyre J.A., Kamboh M.I.;
RT "Identification of structural mutations in the fifth domain of
RT apolipoprotein H (beta-2-glycoprotein I) which affect phospholipid
RT binding.";
RL Hum. Mol. Genet. 6:311-316(1997).
CC -!- FUNCTION: Binds to various kinds of negatively charged substances
CC such as heparin, phospholipids, and dextran sulfate. May prevent
CC activation of the intrinsic blood coagulation cascade by binding
CC to phospholipids on the surface of damaged cells.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-2114682, EBI-2114682;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- PTM: N- and O-glycosylated. PubMed:6587378 also reports
CC glycosylation on 'Asn-188' for their allele.
CC -!- SIMILARITY: Contains 4 Sushi (CCP/SCR) domains.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/apoh/";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=APOH";
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DR EMBL; X58100; CAA41113.1; -; mRNA.
DR EMBL; X53595; CAA37664.1; -; mRNA.
DR EMBL; X57847; CAA40977.1; -; mRNA.
DR EMBL; M62839; AAA51766.1; -; mRNA.
DR EMBL; S80305; AAB21330.1; -; mRNA.
DR EMBL; Y11493; CAA72279.1; -; Genomic_DNA.
DR EMBL; Y11494; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y11495; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; X53595; CAA72279.1; JOINED; mRNA.
DR EMBL; Y11496; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y11497; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y11498; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y17754; CAA76845.1; -; Genomic_DNA.
DR EMBL; AK313838; BAG36570.1; -; mRNA.
DR EMBL; AY322156; AAP72014.1; -; Genomic_DNA.
DR EMBL; BC020703; AAH20703.1; -; mRNA.
DR EMBL; BC026283; AAH26283.1; -; mRNA.
DR PIR; S17178; NBHU.
DR RefSeq; NP_000033.2; NM_000042.2.
DR UniGene; Hs.445358; -.
DR PDB; 1C1Z; X-ray; 2.87 A; A=20-345.
DR PDB; 1G4F; NMR; -; A=261-345.
DR PDB; 1G4G; NMR; -; A=261-345.
DR PDB; 1QUB; X-ray; 2.70 A; A=20-329.
DR PDB; 2KRI; NMR; -; A=263-345.
DR PDB; 3OP8; X-ray; 1.90 A; A/B=263-345.
DR PDB; 4JHS; X-ray; 3.00 A; A=203-345.
DR PDBsum; 1C1Z; -.
DR PDBsum; 1G4F; -.
DR PDBsum; 1G4G; -.
DR PDBsum; 1QUB; -.
DR PDBsum; 2KRI; -.
DR PDBsum; 3OP8; -.
DR PDBsum; 4JHS; -.
DR ProteinModelPortal; P02749; -.
DR SMR; P02749; 20-345.
DR DIP; DIP-46878N; -.
DR IntAct; P02749; 8.
DR MINT; MINT-6743724; -.
DR STRING; 9606.ENSP00000205948; -.
DR BindingDB; P02749; -.
DR PhosphoSite; P02749; -.
DR DMDM; 543826; -.
DR PaxDb; P02749; -.
DR PeptideAtlas; P02749; -.
DR PRIDE; P02749; -.
DR DNASU; 350; -.
DR Ensembl; ENST00000205948; ENSP00000205948; ENSG00000091583.
DR GeneID; 350; -.
DR KEGG; hsa:350; -.
DR UCSC; uc002jfn.4; human.
DR CTD; 350; -.
DR GeneCards; GC17M064208; -.
DR HGNC; HGNC:616; APOH.
DR HPA; CAB022214; -.
DR HPA; HPA001654; -.
DR HPA; HPA003732; -.
DR MIM; 138700; gene.
DR neXtProt; NX_P02749; -.
DR PharmGKB; PA24903; -.
DR eggNOG; NOG323950; -.
DR HOGENOM; HOG000034008; -.
DR HOVERGEN; HBG004271; -.
DR InParanoid; P02749; -.
DR KO; K17305; -.
DR OMA; RFTCPLT; -.
DR OrthoDB; EOG7K6PV8; -.
DR PhylomeDB; P02749; -.
DR ChiTaRS; APOH; human.
DR EvolutionaryTrace; P02749; -.
DR GeneWiki; Apolipoprotein_H; -.
DR GenomeRNAi; 350; -.
DR NextBio; 1441; -.
DR PMAP-CutDB; P02749; -.
DR PRO; PR:P02749; -.
DR ArrayExpress; P02749; -.
DR Bgee; P02749; -.
DR CleanEx; HS_APOH; -.
DR Genevestigator; P02749; -.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL.
DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0060230; F:lipoprotein lipase activator activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; IDA:BHF-UCL.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:BHF-UCL.
DR GO; GO:0030195; P:negative regulation of blood coagulation; IDA:BHF-UCL.
DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0033033; P:negative regulation of myeloid cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0034392; P:negative regulation of smooth muscle cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0031639; P:plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0051006; P:positive regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0006641; P:triglyceride metabolic process; IDA:BHF-UCL.
DR GO; GO:0034197; P:triglyceride transport; ISS:BHF-UCL.
DR InterPro; IPR015104; Sushi_2.
DR InterPro; IPR000436; Sushi_SCR_CCP.
DR Pfam; PF00084; Sushi; 4.
DR Pfam; PF09014; Sushi_2; 1.
DR ProDom; PD012422; Sushi_2; 1.
DR SMART; SM00032; CCP; 4.
DR SUPFAM; SSF57535; SSF57535; 5.
DR PROSITE; PS50923; SUSHI; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Heparin-binding; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal; Sushi.
FT SIGNAL 1 19
FT CHAIN 20 345 Beta-2-glycoprotein 1.
FT /FTId=PRO_0000002059.
FT DOMAIN 21 81 Sushi 1.
FT DOMAIN 82 139 Sushi 2.
FT DOMAIN 140 202 Sushi 3.
FT DOMAIN 203 262 Sushi 4.
FT REGION 263 345 Sushi-like.
FT CARBOHYD 149 149 O-linked (GalNAc...).
FT CARBOHYD 162 162 N-linked (GlcNAc...) (complex).
FT CARBOHYD 183 183 N-linked (GlcNAc...).
FT CARBOHYD 193 193 N-linked (GlcNAc...).
FT CARBOHYD 253 253 N-linked (GlcNAc...).
FT DISULFID 23 66
FT DISULFID 51 79
FT DISULFID 84 124
FT DISULFID 110 137
FT DISULFID 142 188
FT DISULFID 174 200
FT DISULFID 205 248
FT DISULFID 234 260
FT DISULFID 264 315
FT DISULFID 300 325
FT DISULFID 307 345
FT VARIANT 5 5 V -> A (in dbSNP:rs3826358).
FT /FTId=VAR_048316.
FT VARIANT 107 107 S -> N (in allele APOH*1;
FT dbSNP:rs1801692).
FT /FTId=VAR_008169.
FT VARIANT 154 154 R -> H (in dbSNP:rs8178847).
FT /FTId=VAR_019155.
FT VARIANT 266 266 V -> L (in 23% of the population;
FT dbSNP:rs4581).
FT /FTId=VAR_000673.
FT VARIANT 325 325 C -> G (loss of phosphatidylserine-
FT binding; dbSNP:rs1801689).
FT /FTId=VAR_008170.
FT VARIANT 335 335 W -> S (in allele APOH*3W; loss of
FT phosphatidylserine-binding;
FT dbSNP:rs1801690).
FT /FTId=VAR_008171.
FT CONFLICT 121 121 S -> C (in Ref. 10; AA sequence).
FT CONFLICT 188 188 C -> N (in Ref. 10; AA sequence).
FT STRAND 22 24
FT STRAND 32 36
FT STRAND 39 41
FT STRAND 46 51
FT STRAND 55 57
FT STRAND 62 65
FT STRAND 79 81
FT STRAND 93 96
FT STRAND 105 110
FT STRAND 114 118
FT STRAND 120 124
FT STRAND 130 132
FT STRAND 136 139
FT STRAND 151 155
FT STRAND 163 165
FT STRAND 169 174
FT STRAND 178 182
FT STRAND 184 188
FT STRAND 192 195
FT STRAND 199 202
FT STRAND 214 217
FT STRAND 222 225
FT STRAND 229 234
FT STRAND 238 242
FT STRAND 244 248
FT STRAND 252 255
FT STRAND 260 262
FT STRAND 267 270
FT STRAND 272 275
FT STRAND 278 281
FT HELIX 282 285
FT TURN 286 288
FT STRAND 295 302
FT TURN 303 306
FT STRAND 307 316
FT TURN 331 333
FT HELIX 339 341
SQ SEQUENCE 345 AA; 38298 MW; 63101704F8EDFE3F CRC64;
MISPVLILFS SFLCHVAIAG RTCPKPDDLP FSTVVPLKTF YEPGEEITYS CKPGYVSRGG
MRKFICPLTG LWPINTLKCT PRVCPFAGIL ENGAVRYTTF EYPNTISFSC NTGFYLNGAD
SAKCTEEGKW SPELPVCAPI ICPPPSIPTF ATLRVYKPSA GNNSLYRDTA VFECLPQHAM
FGNDTITCTT HGNWTKLPEC REVKCPFPSR PDNGFVNYPA KPTLYYKDKA TFGCHDGYSL
DGPEEIECTK LGNWSAMPSC KASCKVPVKK ATVVYQGERV KIQEKFKNGM LHGDKVSFFC
KNKEKKCSYT EDAQCIDGTI EVPKCFKEHS SLAFWKTDAS DVKPC
//
ID APOH_HUMAN Reviewed; 345 AA.
AC P02749; B2R9M3; Q9UCN7;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 3.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Beta-2-glycoprotein 1;
DE AltName: Full=APC inhibitor;
DE AltName: Full=Activated protein C-binding protein;
DE AltName: Full=Anticardiolipin cofactor;
DE AltName: Full=Apolipoprotein H;
DE Short=Apo-H;
DE AltName: Full=Beta-2-glycoprotein I;
DE Short=B2GPI;
DE Short=Beta(2)GPI;
DE Flags: Precursor;
GN Name=APOH; Synonyms=B2G1;
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=1650181;
RA Steinkasserer A., Estaller C., Weiss E., Sim R.B., Day A.J.;
RT "Complete nucleotide and deduced amino acid sequence of human beta 2-
RT glycoprotein I.";
RL Biochem. J. 277:387-391(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1655523; DOI=10.1016/0014-5793(91)81065-G;
RA Kristensen T., Schousboe I., Boel E., Mulvihill E.M., Hansen R.R.,
RA Moeller K.B., Moeller N.P.H., Sottrup-Jensen L.;
RT "Molecular cloning and mammalian expression of human beta 2-
RT glycoprotein I cDNA.";
RL FEBS Lett. 289:183-186(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1748314; DOI=10.1016/0378-1119(91)90449-L;
RA Mehdi H., Nunn M., Steel D.M., Whitehead A.S., Perez M., Walker L.,
RA Peeples M.E.;
RT "Nucleotide sequence and expression of the human gene encoding
RT apolipoprotein H (beta 2-glycoprotein I).";
RL Gene 108:293-298(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1339416; DOI=10.1007/BF02591656;
RA Day J.R., O'Hara P.J., Grant F.J., Lofton-Day C.E., Berkaw M.N.,
RA Werner P., Arnaud P.;
RT "Molecular cloning and sequence analysis of the cDNA encoding human
RT apolipoprotein H (beta 2-glycoprotein I).";
RL Int. J. Clin. Lab. Res. 21:256-263(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1777418; DOI=10.1093/intimm/3.12.1217;
RA Matsuura E., Igarashi M., Igarashi Y., Nagae H., Ichikawa K.,
RA Yasuda T., Koike T.;
RT "Molecular definition of human beta 2-glycoprotein I (beta 2-GPI) by
RT cDNA cloning and inter-species differences of beta 2-GPI in
RT alternation of anticardiolipin binding.";
RL Int. Immunol. 3:1217-1221(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9914524; DOI=10.1046/j.1432-1327.1999.00063.x;
RA Okkels H., Rasmussen T.E., Sanghera D.K., Kamboh M.I., Kristensen T.;
RT "Structure of the human beta2-glycoprotein I (apolipoprotein H)
RT gene.";
RL Eur. J. Biochem. 259:435-440(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-107.
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASN-107; HIS-154;
RP LEU-266 AND SER-335.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [10]
RP PROTEIN SEQUENCE OF 20-345, GLYCOSYLATION AT ASN-162; ASN-183; ASN-193
RP AND ASN-253, AND DISULFIDE BONDS.
RX PubMed=6587378; DOI=10.1073/pnas.81.12.3640;
RA Lozier J., Takahashi N., Putnam F.W.;
RT "Complete amino acid sequence of human plasma beta 2-glycoprotein I.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:3640-3644(1984).
RN [11]
RP PROTEIN SEQUENCE OF 20-44.
RX PubMed=1602135;
RA Matsuura E., Igarashi Y., Fujimoto M., Ichikawa K., Suzuki T.,
RA Sumida T., Yasuda T., Koike T.;
RT "Heterogeneity of anticardiolipin antibodies defined by the
RT anticardiolipin cofactor.";
RL J. Immunol. 148:3885-3891(1992).
RN [12]
RP PROTEIN SEQUENCE OF 20-43.
RX PubMed=2349221; DOI=10.1073/pnas.87.11.4120;
RA McNeil H.P., Simpson R.J., Chesterman C.N., Krilis S.A.;
RT "Anti-phospholipid antibodies are directed against a complex antigen
RT that includes a lipid-binding inhibitor of coagulation: beta 2-
RT glycoprotein I (apolipoprotein H).";
RL Proc. Natl. Acad. Sci. U.S.A. 87:4120-4124(1990).
RN [13]
RP PROTEIN SEQUENCE OF 20-38.
RC TISSUE=Ovarian follicular fluid;
RX PubMed=11250549; DOI=10.1016/S1096-4959(00)00359-6;
RA Aleporou-Marinou V., Pappa H., Yalouris P., Patargias T.;
RT "Purification of apolipoprotein H (beta 2-glycoprotein I)-like protein
RT from human follicular fluid.";
RL Comp. Biochem. Physiol. 128B:537-542(2001).
RN [14]
RP DISULFIDE BONDS IN C-TERMINAL DOMAIN.
RX PubMed=1426288; DOI=10.1016/0014-5793(92)81442-O;
RA Steinkkasserer A., Barlow P.N., Willis A.C., Kertesz Z.,
RA Campbell I.D., Sim R.B., Norman D.G.;
RT "Activity, disulphide mapping and structural modelling of the fifth
RT domain of human beta 2-glycoprotein I.";
RL FEBS Lett. 313:193-197(1992).
RN [15]
RP STRUCTURE OF CARBOHYDRATES.
RX PubMed=9155091; DOI=10.1023/A:1026378825391;
RA Gambino R., Ruiu G., Pagano G., Cassader M.;
RT "Qualitative analysis of the carbohydrate composition of
RT apolipoprotein H.";
RL J. Protein Chem. 16:205-212(1997).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162 AND ASN-253, AND MASS
RP SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162; ASN-183 AND ASN-193,
RP AND MASS 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 [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162; ASN-183; ASN-193 AND
RP ASN-253, AND MASS 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 [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162 AND ASN-253, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162; ASN-183; ASN-193 AND
RP ASN-253, AND MASS 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 [21]
RP GLYCOSYLATION AT ASN-162.
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.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-162, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
RC TISSUE=Plasma;
RX PubMed=10508150; DOI=10.1093/emboj/18.19.5166;
RA Bouma B., de Groot P.G., van Den Elsen J.M.H., Ravelli R.B.G.,
RA Schouten A., Simmelink M.J.A., Derksen R.H.W.M., Kroon J., Gros P.;
RT "Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids
RT based on its crystal structure.";
RL EMBO J. 18:5166-5174(1999).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.87 ANGSTROMS).
RX PubMed=10562535; DOI=10.1093/emboj/18.22.6228;
RA Schwarzenbacher R., Zeth K., Diederichs K., Gries A., Kostner G.M.,
RA Laggner P., Prassl R.;
RT "Crystal structure of human beta2-glycoprotein I: implications for
RT phospholipid binding and the antiphospholipid syndrome.";
RL EMBO J. 18:6228-6239(1999).
RN [26]
RP VARIANT LEU-266.
RX PubMed=8099061; DOI=10.1007/BF00217367;
RA Steinkasserer A., Doerner C., Wuerzner R., Sim R.B.;
RT "Human beta 2-glycoprotein I: molecular analysis of DNA and amino acid
RT polymorphism.";
RL Hum. Genet. 91:401-402(1993).
RN [27]
RP VARIANT ASN-107.
RX PubMed=9225969; DOI=10.1007/s004390050465;
RA Sanghera D.K., Kristensen T., Hamman R.F., Kamboh M.I.;
RT "Molecular basis of the apolipoprotein H (beta 2-glycoprotein I)
RT protein polymorphism.";
RL Hum. Genet. 100:57-62(1997).
RN [28]
RP VARIANTS GLY-325 AND SER-335.
RX PubMed=9063752; DOI=10.1093/hmg/6.2.311;
RA Sanghera D.K., Wagenknecht D.R., McIntyre J.A., Kamboh M.I.;
RT "Identification of structural mutations in the fifth domain of
RT apolipoprotein H (beta-2-glycoprotein I) which affect phospholipid
RT binding.";
RL Hum. Mol. Genet. 6:311-316(1997).
CC -!- FUNCTION: Binds to various kinds of negatively charged substances
CC such as heparin, phospholipids, and dextran sulfate. May prevent
CC activation of the intrinsic blood coagulation cascade by binding
CC to phospholipids on the surface of damaged cells.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-2114682, EBI-2114682;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- PTM: N- and O-glycosylated. PubMed:6587378 also reports
CC glycosylation on 'Asn-188' for their allele.
CC -!- SIMILARITY: Contains 4 Sushi (CCP/SCR) domains.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/apoh/";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=APOH";
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DR EMBL; X58100; CAA41113.1; -; mRNA.
DR EMBL; X53595; CAA37664.1; -; mRNA.
DR EMBL; X57847; CAA40977.1; -; mRNA.
DR EMBL; M62839; AAA51766.1; -; mRNA.
DR EMBL; S80305; AAB21330.1; -; mRNA.
DR EMBL; Y11493; CAA72279.1; -; Genomic_DNA.
DR EMBL; Y11494; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y11495; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; X53595; CAA72279.1; JOINED; mRNA.
DR EMBL; Y11496; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y11497; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y11498; CAA72279.1; JOINED; Genomic_DNA.
DR EMBL; Y17754; CAA76845.1; -; Genomic_DNA.
DR EMBL; AK313838; BAG36570.1; -; mRNA.
DR EMBL; AY322156; AAP72014.1; -; Genomic_DNA.
DR EMBL; BC020703; AAH20703.1; -; mRNA.
DR EMBL; BC026283; AAH26283.1; -; mRNA.
DR PIR; S17178; NBHU.
DR RefSeq; NP_000033.2; NM_000042.2.
DR UniGene; Hs.445358; -.
DR PDB; 1C1Z; X-ray; 2.87 A; A=20-345.
DR PDB; 1G4F; NMR; -; A=261-345.
DR PDB; 1G4G; NMR; -; A=261-345.
DR PDB; 1QUB; X-ray; 2.70 A; A=20-329.
DR PDB; 2KRI; NMR; -; A=263-345.
DR PDB; 3OP8; X-ray; 1.90 A; A/B=263-345.
DR PDB; 4JHS; X-ray; 3.00 A; A=203-345.
DR PDBsum; 1C1Z; -.
DR PDBsum; 1G4F; -.
DR PDBsum; 1G4G; -.
DR PDBsum; 1QUB; -.
DR PDBsum; 2KRI; -.
DR PDBsum; 3OP8; -.
DR PDBsum; 4JHS; -.
DR ProteinModelPortal; P02749; -.
DR SMR; P02749; 20-345.
DR DIP; DIP-46878N; -.
DR IntAct; P02749; 8.
DR MINT; MINT-6743724; -.
DR STRING; 9606.ENSP00000205948; -.
DR BindingDB; P02749; -.
DR PhosphoSite; P02749; -.
DR DMDM; 543826; -.
DR PaxDb; P02749; -.
DR PeptideAtlas; P02749; -.
DR PRIDE; P02749; -.
DR DNASU; 350; -.
DR Ensembl; ENST00000205948; ENSP00000205948; ENSG00000091583.
DR GeneID; 350; -.
DR KEGG; hsa:350; -.
DR UCSC; uc002jfn.4; human.
DR CTD; 350; -.
DR GeneCards; GC17M064208; -.
DR HGNC; HGNC:616; APOH.
DR HPA; CAB022214; -.
DR HPA; HPA001654; -.
DR HPA; HPA003732; -.
DR MIM; 138700; gene.
DR neXtProt; NX_P02749; -.
DR PharmGKB; PA24903; -.
DR eggNOG; NOG323950; -.
DR HOGENOM; HOG000034008; -.
DR HOVERGEN; HBG004271; -.
DR InParanoid; P02749; -.
DR KO; K17305; -.
DR OMA; RFTCPLT; -.
DR OrthoDB; EOG7K6PV8; -.
DR PhylomeDB; P02749; -.
DR ChiTaRS; APOH; human.
DR EvolutionaryTrace; P02749; -.
DR GeneWiki; Apolipoprotein_H; -.
DR GenomeRNAi; 350; -.
DR NextBio; 1441; -.
DR PMAP-CutDB; P02749; -.
DR PRO; PR:P02749; -.
DR ArrayExpress; P02749; -.
DR Bgee; P02749; -.
DR CleanEx; HS_APOH; -.
DR Genevestigator; P02749; -.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL.
DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0060230; F:lipoprotein lipase activator activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; IDA:BHF-UCL.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:BHF-UCL.
DR GO; GO:0030195; P:negative regulation of blood coagulation; IDA:BHF-UCL.
DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0033033; P:negative regulation of myeloid cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0034392; P:negative regulation of smooth muscle cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0031639; P:plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0051006; P:positive regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0006641; P:triglyceride metabolic process; IDA:BHF-UCL.
DR GO; GO:0034197; P:triglyceride transport; ISS:BHF-UCL.
DR InterPro; IPR015104; Sushi_2.
DR InterPro; IPR000436; Sushi_SCR_CCP.
DR Pfam; PF00084; Sushi; 4.
DR Pfam; PF09014; Sushi_2; 1.
DR ProDom; PD012422; Sushi_2; 1.
DR SMART; SM00032; CCP; 4.
DR SUPFAM; SSF57535; SSF57535; 5.
DR PROSITE; PS50923; SUSHI; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Heparin-binding; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal; Sushi.
FT SIGNAL 1 19
FT CHAIN 20 345 Beta-2-glycoprotein 1.
FT /FTId=PRO_0000002059.
FT DOMAIN 21 81 Sushi 1.
FT DOMAIN 82 139 Sushi 2.
FT DOMAIN 140 202 Sushi 3.
FT DOMAIN 203 262 Sushi 4.
FT REGION 263 345 Sushi-like.
FT CARBOHYD 149 149 O-linked (GalNAc...).
FT CARBOHYD 162 162 N-linked (GlcNAc...) (complex).
FT CARBOHYD 183 183 N-linked (GlcNAc...).
FT CARBOHYD 193 193 N-linked (GlcNAc...).
FT CARBOHYD 253 253 N-linked (GlcNAc...).
FT DISULFID 23 66
FT DISULFID 51 79
FT DISULFID 84 124
FT DISULFID 110 137
FT DISULFID 142 188
FT DISULFID 174 200
FT DISULFID 205 248
FT DISULFID 234 260
FT DISULFID 264 315
FT DISULFID 300 325
FT DISULFID 307 345
FT VARIANT 5 5 V -> A (in dbSNP:rs3826358).
FT /FTId=VAR_048316.
FT VARIANT 107 107 S -> N (in allele APOH*1;
FT dbSNP:rs1801692).
FT /FTId=VAR_008169.
FT VARIANT 154 154 R -> H (in dbSNP:rs8178847).
FT /FTId=VAR_019155.
FT VARIANT 266 266 V -> L (in 23% of the population;
FT dbSNP:rs4581).
FT /FTId=VAR_000673.
FT VARIANT 325 325 C -> G (loss of phosphatidylserine-
FT binding; dbSNP:rs1801689).
FT /FTId=VAR_008170.
FT VARIANT 335 335 W -> S (in allele APOH*3W; loss of
FT phosphatidylserine-binding;
FT dbSNP:rs1801690).
FT /FTId=VAR_008171.
FT CONFLICT 121 121 S -> C (in Ref. 10; AA sequence).
FT CONFLICT 188 188 C -> N (in Ref. 10; AA sequence).
FT STRAND 22 24
FT STRAND 32 36
FT STRAND 39 41
FT STRAND 46 51
FT STRAND 55 57
FT STRAND 62 65
FT STRAND 79 81
FT STRAND 93 96
FT STRAND 105 110
FT STRAND 114 118
FT STRAND 120 124
FT STRAND 130 132
FT STRAND 136 139
FT STRAND 151 155
FT STRAND 163 165
FT STRAND 169 174
FT STRAND 178 182
FT STRAND 184 188
FT STRAND 192 195
FT STRAND 199 202
FT STRAND 214 217
FT STRAND 222 225
FT STRAND 229 234
FT STRAND 238 242
FT STRAND 244 248
FT STRAND 252 255
FT STRAND 260 262
FT STRAND 267 270
FT STRAND 272 275
FT STRAND 278 281
FT HELIX 282 285
FT TURN 286 288
FT STRAND 295 302
FT TURN 303 306
FT STRAND 307 316
FT TURN 331 333
FT HELIX 339 341
SQ SEQUENCE 345 AA; 38298 MW; 63101704F8EDFE3F CRC64;
MISPVLILFS SFLCHVAIAG RTCPKPDDLP FSTVVPLKTF YEPGEEITYS CKPGYVSRGG
MRKFICPLTG LWPINTLKCT PRVCPFAGIL ENGAVRYTTF EYPNTISFSC NTGFYLNGAD
SAKCTEEGKW SPELPVCAPI ICPPPSIPTF ATLRVYKPSA GNNSLYRDTA VFECLPQHAM
FGNDTITCTT HGNWTKLPEC REVKCPFPSR PDNGFVNYPA KPTLYYKDKA TFGCHDGYSL
DGPEEIECTK LGNWSAMPSC KASCKVPVKK ATVVYQGERV KIQEKFKNGM LHGDKVSFFC
KNKEKKCSYT EDAQCIDGTI EVPKCFKEHS SLAFWKTDAS DVKPC
//
MIM
138700
*RECORD*
*FIELD* NO
138700
*FIELD* TI
*138700 APOLIPOPROTEIN H; APOH
;;GLYCOPROTEIN I, BETA-2; B2GP1;;
GLYCOPROTEIN 1, BETA-2;;
read moreBG
*FIELD* TX
DESCRIPTION
The APOH gene encodes beta-2 glycoprotein I, also known as
apolipoprotein H, a single-chain plasma protein of about 50 kD. Beta-2
GPI binds to and neutralizes negatively charged phospholipid
macromolecules, thereby diminishing inappropriate activation of the
intrinsic blood coagulation cascade. Beta-2 GPI has been implicated in a
variety of physiologic pathways, including blood coagulation,
hemostasis, and the production of antiphospholipid antibodies
characteristic of antiphospholipid syndrome (APS; 107320) (summary by
Mehdi et al., 2003).
CLONING
Lozier et al. (1984) determined the full amino acid sequence of
beta-2-glycoprotein (apoH). The deduced 326-amino acid protein contains
5 attached glucosamine-containing oligosaccharides. Computerized
analysis of the sequence revealed 5 consecutive homologous segments in
which cysteine, proline, and tryptophan appeared to be highly conserved.
Mehdi et al. (1991) cloned and sequenced APOH cDNAs from human liver and
from a human hepatoma cell line. Both cDNAs predicted a protein of 345
amino acids, including a 19-amino acid hydrophobic, N-terminal signal
sequence that is not present in the mature protein. The level of APOH
mRNA expressed by the hepatoma cells was downregulated by incubation
with inflammatory mediators, implying that APOH is a negative
acute-phase protein.
By Northern blot analysis, Steinkasserer et al. (1992) established that
APOH is synthesized in the liver where a transcript of approximately 1.5
kb was identified.
Sanghera et al. (2001) found that the chimpanzee APOH gene encodes a
deduced 326-amino acid protein, as in humans. The human and chimpanzee
APOH proteins share 99.4% sequence similarity.
GENE STRUCTURE
Sheng et al. (1997) found that the mouse Apoh gene contains 8 exons and
spans approximately 18 kb.
Sanghera et al. (2001) found that the chimpanzee APOH gene, like the
human gene, contains 8 exons.
MAPPING
Haagerup et al. (1991) demonstrated RFLPs in the APOH gene and used
these in CEPH family studies to locate the gene on 17q. The marker that
showed closest linkage was HOX2 (142960), located at 17q21-q22; lod
score = 8.83 at theta = 0.05. Linkage to COL1A1 (120150) was indicated
by a lod score of 6.18 at theta = 0.12. By hybridizing a cDNA probe for
APOH to a panel of somatic cell hybrids, Steinkasserer et al. (1992)
showed that the structural locus maps to 17q23-qter.
Nonaka et al. (1992) mapped the mouse Apoh gene to chromosome 11. Nonaka
et al. (1992) commented that the mouse Apoh protein is composed of 5
repeating units called short consensus repeats (SCR), which are found
mostly in the regulatory proteins of the complement system.
GENE FUNCTION
Nakaya et al. (1980) demonstrated beta-2-glycoprotein I activation of
lipoprotein lipase and designated this glycoprotein as apolipoprotein H.
Lozier et al. (1984) noted that B2GI is associated with lipoproteins,
binds to platelets, interacts with heparin, and may be involved in blood
coagulation.
McNeil et al. (1990) identified beta-2-glycoprotein I as a cofactor
required for antiphospholipid antibodies (APA) to bind to cardiolipin.
These findings suggested that APA are directed against a complex antigen
that includes B2GPI. In addition, B2GPI bound to anionic phospholipids
in the absence of anticardiolipin antibodies. McNeil et al. (1990)
hypothesized that anticardiolipin APA may interfere with the function of
apoH in vivo, which may explain the association of these antibodies with
thrombotic tendencies.
Sanghera et al. (1997) noted that apoH had been implicated in a variety
of physiologic pathways including lipoprotein metabolism, coagulation,
and the production of antiphospholipid autoantibodies. They cited
reports supporting the conclusion that apoH is a required cofactor for
anionic phospholipid binding by the antiphospholipid autoantibodies
found in sera of many patients with systemic lupus erythematosus (SLE;
152700) and primary antiphospholipid syndrome (107320), but it does not
seem to be required for the reactivity of antiphospholipid
autoantibodies associated with infections. These studies suggested that
the apoH-phospholipid complex forms the antigen to which the
autoantibodies are directed. Sanghera et al. (1997) postulated that
genetically determined structural abnormalities in the lipid-binding
domain(s) of apoH may affect its ability to bind lipid and consequently
the production of the autoantibodies.
Agar et al. (2010) used electron microscopy to demonstrate that B2GPI
exists in at least 2 different conformations: a closed circular plasma
conformation and an activated open conformation. The closed circular
conformation is maintained by interaction between the first (DI) and
fifth (DV) domains. In the activated open conformation, a cryptic
epitope in the first domain becomes exposed that enables antibodies to
bind and form an antibody-B2GPI complex. The open conformation prolonged
the activated partial thromboplastin time (APTT) when added to normal
plasma, and the APTT was further prolonged by addition of anti-B2GPI
antibodies, consistent with an anticoagulant effect. The conformations
could be converted into each other by changing pH and salt
concentrations.
In a review, Giannakopoulos et al. (2011) noted that B2GPI contains
multiple cysteine residues that mediate platelet and endothelial cell
adhesion via thiol exchange reactions. Evidence also suggests that B2GPI
may play a role in apoptosis by binding to blebs on apoptotic cells.
MOLECULAR GENETICS
Richter and Cleve (1988) demonstrated genetic variation of APOH by means
of isoelectric focusing, and data on gene frequencies of allelic
variants were tabulated by Roychoudhury and Nei (1988).
Using thin-layer polyacrylamide isoelectric focusing gels and
immunologic identification, Kamboh et al. (1988) demonstrated
genetically determined polymorphism of apolipoprotein H. Three common
alleles were identified in U.S. whites and blacks. A fourth allele was
observed in individuals of African descent. Family data confirmed
autosomal codominant inheritance of 4 alleles at a single APOH locus.
Sepehrnia et al. (1988) provided data on the distribution of
apolipoprotein polymorphisms in Nigeria, including polymorphism of APOH.
The observations supported the conclusion that the APOH*4 is a marker
allele unique to blacks and one that may be widely distributed among
African populations, whereas the APOH*1 allele may be a unique Caucasian
allele that was introduced into the black population of the U.S. by
admixture.
Eiberg et al. (1989) reported linkage data suggesting that the
structural and quantitative polymorphisms associated with serum
beta-2-glycoprotein I were very tightly linked (maximum lod score = 3.28
at theta = 0.0, male and female data combined). Sepehrnia et al. (1989)
found specific associations between particular APOH alleles and the
level of triglycerides in females.
In a population of black Africans from the Ivory Coast, Cleve et al.
(1992) found that the gene frequencies of APOH*1, APOH*2, APOH*3, and
APOH*4 were 0.012, 0.921, 0.047, and 0.020, respectively. In a tabular
review of reported frequencies in different populations, APOH*4 was
found only in individuals of African descent. The most common allele in
all populations, including African, Caucasian, European, and East Asian
descent, was APOH*2.
Among 661 non-Hispanic whites, Sanghera et al. (1997) found that the
frequency of the APOH*1, APOH*2, and APOH*3 alleles were 0.059, 0.868,
and 0.073, respectively. Sanghera et al. (1997) determined that the
APOH*1 allele is due to a ser88-to-asn (S88N) substitution in exon 3 of
the APOH gene. The frequency of the asn88 allele was 0.011, 0.043, and
0.056 in blacks, Hispanics, and non-Hispanic whites, respectively. Based
upon reactivity with a certain monoclonal apoH antibody, the APOH*3
allele could be subdivided into APOH*3(W) (reactive) and APOH*3(B)
(non-reactive). The APOH*3(W) allele was found to result from a
trp316-to-ser (W316S) substitution in the APOH gene. White had a
significantly higher frequency of APOH*3(W) (0.059) compared to blacks
(0.008).
Sanghera et al. (1997) found that the W316S substitution in the APOH
gene occurs in the fifth domain (domain V) of the protein, which affects
phospholipid binding. Another structural substitution in this domain,
cys306-to-gly (C306G), was also shown to disrupt binding of APOH to
phospholipid. These data indicated that domain V of APOH harbors the
lipid-binding region.
Among 455 non-Hispanic individuals, Mehdi et al. (1999) found that the
APOH*3(W) allele was associated with decreased plasma levels of apoH and
was estimated to account for about 10% of the phenotypic variation in
plasma levels in both men and women. However, Mehdi et al. (2003) found
that the W316S allele was in linkage disequilibrium with a promoter
polymorphism in the APOH gene, which explained the variation in plasma
apoH levels.
Hirose et al. (1999) found that the val247 allele (138700.0001) was
significantly associated with the presence of anti-B2GPI antibodies in
Asian patients with antiphospholipid syndrome (APS; 107320) in a study
of 370 healthy controls from different racial backgrounds and 149
patients with APS. The V allele and the VV genotype occurred most often
among Caucasians, less among African Americans, and least among Asians.
Conversely, the V allele and the VV genotype were found more frequently
among Asian patients with antiphospholipid syndrome than among controls
(p = 0.0028 and p = 0.0023, respectively). There were no significant
differences in allele or genotype frequencies when comparing Caucasian
or African American APS patients with appropriate controls. The
differences in allele and genotype frequencies seen in Asian APS
patients were restricted to those with anti-B2GPI antibodies.
HISTORY
Haupt et al. (1968) described a family in which 2 brothers had complete
absence of what they termed beta-2-glycoprotein I (Bg) in the serum.
Both parents, a sister, and both children of 1 of the brothers had
half-normal levels of the protein. Cleve and Rittner (1969) found 9
families out of 88 in which 1 parent and about half the children had
intermediate concentrations of beta-2-glycoprotein I, presumed to be
heterozygous for a deficiency ('null') gene.
Hoeg et al. (1985) observed the rare occurrence of total lack of
detectable apoH protein in less than 0.3% of clinic patients. A study of
family members of 5 such patients demonstrated autosomal codominant
inheritance pattern for plasma levels. The authors were impressed by the
lack of consistent effects on other plasma lipoproteins, and concluded
that the lack of apolipoprotein H does not result in a significant
perturbation of normal lipoprotein metabolism, suggesting that the
finding may not have clinical relevance.
Bancsi et al. (1992) concluded that deficiency of plasma B2GPI is not a
risk factor for thrombosis. In a comparison of healthy volunteers and 4
different groups of patients with familial thrombophilia, the prevalence
of B2GPI deficiency (plasma levels less than 77%) was found to be very
similar (6.8-12.5%) and not statistically significant between the
groups. One thrombophilic patient was found to be homozygous-deficient
for B2GPI and this transmission of the defect in his family followed
autosomal inheritance. However, 1 of his brothers was also
homozygous-deficient and was free of thromboembolic complications at the
age of 35 years.
ANIMAL MODEL
Using isoelectric focusing and immunoblotting, Sanghera et al. (2001)
screened 155 chimpanzees (128 unrelated captured parents and 27
captive-born offspring) for the apoH protein polymorphism. The most
common IEF pattern in chimpanzees was identical to a previously
described APOH*3 allele in humans. In addition, they identified in
chimpanzees an allele designated APOH*4, resulting from a lys210-to-glu
missense change in exon 6. They found that the prevalence of anti-apoH
antibodies in chimpanzees (64%) was unusually high compared to that in
humans. No association was found between the lys210-to-glu mutation and
the occurrence of anti-apoH antibodies. The authors suggested that the
chimpanzee may serve as a useful animal model for human antiphospholipid
syndrome (107320).
Sheng et al. (2001) found that B2ghi-null mice were born at lower than
expected frequencies, suggesting that B2gpi may play a role in
implantation. However, B2gpi-null mice themselves did not show
reproductive abnormalities: the number of pregnancies, litter size, and
birth weight was similar to that of heterozygotes and controls.
B2gpi-null mice had no detectable organ pathology, and in vivo
coagulation profiles were also similar to controls. However, in vitro
studies of blood derived from the B2gpi-null mice showed less thrombin
generation compared to heterozygotes or controls.
*FIELD* AV
.0001
APOH POLYMORPHISM
APOH, VAL247LEU
Steinkasserer et al. (1993) described a 2-allele RsaI restriction
fragment length polymorphism (RFLP) in the APOH gene and demonstrated
that it led to a val247-to-leu (V247L) substitution. In studies of 34
unrelated parents in the CEPH family panel, allele frequencies were
found to be 0.76 for valine and 0.23 for leucine. The val-leu
polymorphism did not correlate with the 4 isoelectric focusing alleles
previously described.
*FIELD* SA
Cleve (1968); Eiberg et al. (1984); Koppe et al. (1970); Rahimi et
al. (1977); Walter et al. (1979)
*FIELD* RF
1. Agar, C.; van Os, G. M. A.; Morgelin, M.; Sprenger, R. R.; Marquart,
J. A.; Urbanus, R. T.; Derksen, R. H. W. M.; Meijers, J. C. M.; de
Groot, P. G.: Beta2-glycoprotein I can exist in 2 conformations:
implications for our understanding of the antiphospholipid syndrome. Blood 116:
1336-1343, 2010.
2. Bancsi, L. F. J. M. M.; van der Linden, I. K.; Bertina, R. M.:
Beta-2-glycoprotein I deficiency and the risk of thrombosis. Thromb.
Haemost. 67: 649-653, 1992.
3. Cleve, H.: Genetic studies on the deficiency of beta-2-glycoprotein
I of human serum. Humangenetik 5: 294-304, 1968.
4. Cleve, H.; Rittner, C.: Further family studies on the genetic
control of beta-2-glycoprotein I concentration in human serum. Humangenetik 7:
93-97, 1969.
5. Cleve, H.; Vogt, U.; Kamboh, M. I.: Genetic polymorphism of apolipoprotein
H (beta-2 glycoprotein I) in African blacks from the Ivory Coast. Electrophoresis 13:
849-851, 1992.
6. Eiberg, H.; Mohr, J.; Nielsen, L. S.: The beta-2-glycoprotein
I (BG): allele frequencies and linkage relationships. (Abstract) Cytogenet.
Cell Genet. 37: 462 only, 1984.
7. Eiberg, H.; Nielsen, L. S.; Mohr, J.: Exclusion mapping of apolipoprotein
H (APOH) and relationship between electrophoretic and quantitative
polymorphism. (Abstract) Cytogenet. Cell Genet. 51: 994 only, 1989.
8. Giannakopoulos, B.; Mirarabshahi, P.; Krilis, S. A.: New insights
into the biology and pathobiology of beta2-glycoprotein I. Curr.
Rheum. Rep. 13: 90-95, 2011.
9. Haagerup, A.; Kristensen, T.; Kruse, T. A.: Polymorphism and genetic
mapping of the gene encoding human beta-2-glycoprotein I to chromosome
17. (Abstract) Cytogenet. Cell Genet. 58: 2005 only, 1991.
10. Haupt, H.; Schwick, H. G.; Storiko, K.: Ueber einen erblichen
beta-2-Glykoprotein I-Mangel. Humangenetik 5: 291-293, 1968.
11. Hirose, N.; Williams, R.; Alberts, A. R.; Furie, R. A.; Chartash,
E. K.; Jain, R. I.; Sison, C.; Lahita, R. G.; Merrill, J. T.; Cucurull,
E.; Gharavi, A. E.; Sammaritano, L. R.; Salmon, J. E.; Hashimoto,
S.; Sawada, T.; Chu, C. C.; Gregersen, P. K.; Chiorazzi, N.: A role
for the polymorphism at position 247 of the beta2-glycoprotein I gene
in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid
syndrome. Arthritis Rheum. 42: 1655-1661, 1999.
12. Hoeg, J. M.; Segal, P.; Gregg, R. E.; Chang, Y. S.; Lindgren,
F. T.; Adamson, G. L.; Frank, M.; Brickman, C.; Brewer, H. B., Jr.
: Characterization of plasma lipids and lipoproteins in patients with
beta-2-glycoprotein I (apolipoprotein H) deficiency. Atherosclerosis 55:
25-34, 1985.
13. Kamboh, M. I.; Ferrell, R. E.; Sepehrnia, B.: Genetic studies
of human apolipoproteins. IV. Structural heterogeneity of apolipoprotein
H (beta-2-glycoprotein I). Am. J. Hum. Genet. 42: 452-457, 1988.
14. Koppe, A. L.; Walter, H.; Chopra, V. P.; Bajatzadeh, M.: Investigations
on the genetics and population genetics of the beta-2-glycoprotein
I polymorphism. Humangenetik 9: 164-171, 1970.
15. Lozier, J.; Takahashi, N.; Putnam, F. W.: Complete amino acid
sequence of human plasma beta-2-glycoprotein I. Proc. Nat. Acad.
Sci. 81: 3640-3644, 1984.
16. McNeil, H. P.; Simpson, R. J.; Chesterman, C. N.; Krilis, S. A.
: Anti-phospholipid antibodies are directed against a complex antigen
that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein
I (apolipoprotein H). Proc. Nat. Acad. Sci. 87: 4120-4124, 1990.
17. Mehdi, H.; Aston, C. E.; Sanghera, D. K.; Hamman, R. F.; Kamboh,
M. I.: Genetic variation in the apolipoprotein H (beta-2-glycoprotein
I) gene affects plasma apolipoprotein H concentrations. Hum. Genet. 105:
63-71, 1999.
18. Mehdi, H.; Manzi, S.; Desai, P.; Chen, Q.; Nestlerode, C.; Bontempo,
F.; Strom, S. C.; Zarnegar, R.; Kamboh, M. I.: A functional polymorphism
at the transcriptional initiation site in beta2-glycoprotein I (apolipoprotein
H) associated with reduced gene expression and lower plasma levels
of beta2-glycoprotein I. Europ. J. Biochem. 270: 230-238, 2003.
19. Mehdi, H.; Nunn, M.; Steel, D. M.; Whitehead, A. S.; Perez, M.;
Walker, L.; Peeples, M. E.: Nucleotide sequence and expression of
the human gene encoding apolipoprotein H (beta-2-glycoprotein I). Gene 108:
293-298, 1991.
20. Nakaya, Y.; Schaefer, E. J.; Brewer, H. B.: Activation of human
post-heparin lipase by apolipoprotein H (beta-2-glycoprotein I). Biochem.
Biophys. Res. Commun. 95: 1168-1172, 1980.
21. Nonaka, M.; Matsuda, Y.; Shiroishi, T.; Moriwaki, K.; Nonaka,
M.; Natsuume-Sakai, S.: Molecular cloning of mouse beta-2-glycoprotein
I and mapping of the gene to chromosome 11. Genomics 13: 1082-1087,
1992.
22. Rahimi, A. G.; Goedde, H. W.; Flatz, G.; Kaifie, S.; Benkmann,
H.-G.; Delbruck, H.: Serum protein polymorphisms in four populations
of Afghanistan. Am. J. Hum. Genet. 29: 356-360, 1977.
23. Richter, A.; Cleve, H.: Genetic variations of human serum beta-2-glycoprotein
I demonstrated by isoelectric focusing. Electrophoresis 9: 317-322,
1988.
24. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.
25. Sanghera, D. K.; Kristensen, T.; Hamman, R. F.; Kamboh, M. I.
: Molecular basis of the apolipoprotein H (beta-2-glycoprotein I)
protein polymorphism. Hum. Genet. 100: 57-62, 1997.
26. Sanghera, D. K.; Nestlerode, C. S.; Ferrell, R. E.; Kamboh, M.
I.: Chimpanzee apolipoprotein H (beta-2-glycoprotein I): report on
the gene structure, a common polymorphism, and a high prevalence of
antiphospholipid antibodies. Hum. Genet. 109: 63-72, 2001.
27. Sanghera, D. K.; Wagenknecht, D. R.; McIntyre, J. A.; Kamboh,
M. I.: Identification of structural mutations in the fifth domain
of apolipoprotein H (beta-2-glycoprotein I) which affect phospholipid
binding. Hum. Molec. Genet. 6: 311-316, 1997.
28. Sepehrnia, B.; Kamboh, M. I.; Adams-Campbell, L. L.; Bunker, C.
H.; Nwankwo, M.; Majumder, P. P.; Ferrell, R. E.: Genetic studies
of human apolipoproteins. VIII. Role of the apolipoprotein H polymorphism
in relation to serum lipoprotein concentrations. Hum. Genet. 82:
118-122, 1989.
29. Sepehrnia, B.; Kamboh, M. I.; Adams-Campbell, L. L.; Nwankwo,
M.; Ferrell, R. E.: Genetic studies of human apolipoproteins. VII.
Population distribution of polymorphisms of apolipoproteins A-I, A-II,
A-IV, C-II, E, and H in Nigeria. Am. J. Hum. Genet. 43: 847-853,
1988.
30. Sheng, Y.; Herzog, H.; Krilis, S. A.: Cloning and characterization
of the gene encoding the mouse beta-2-glycoprotein I. Genomics 41:
128-130, 1997.
31. Sheng, Y.; Reddel, S. W.; Herzog, H.; Wang, Y. X.; Brighton, T.;
France, M. P.; Robertson, S. A.; Krilis, S. A.: Impaired thrombin
generation in beta-2-glycoprotein I null mice. J. Biol. Chem. 276:
13817-13821, 2001.
32. Steinkasserer, A.; Cockburn, D. J.; Black, D. M.; Boyd, Y.; Solomon,
E.; Sim, R. B.: Assignment of apolipoprotein H (APOH: beta-2-glycoprotein
I) to human chromosome 17q23-qter; determination of the major expression
site. Cytogenet. Cell Genet. 60: 31-33, 1992.
33. Steinkasserer, A.; Dorner, C.; Wurzner, R.; Sim, R. B.: Human
beta-2-glycoprotein I: molecular analysis of DNA and amino acid polymorphism. Hum.
Genet. 91: 401-402, 1993.
34. Walter, H.; Hilling, M.; Brachtel, R.; Hitzeroth, H. W.: On the
population genetics of beta-2-glycoprotein I. Hum. Hered. 29: 236-241,
1979.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/13/2011
Cassandra L. Kniffin - updated: 1/14/2011
Rebekah S. Rasooly - updated: 5/7/1998
Victor A. McKusick - updated: 4/21/1997
Victor A. McKusick - updated: 4/15/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 06/24/2011
ckniffin: 6/13/2011
terry: 2/18/2011
carol: 1/24/2011
ckniffin: 1/14/2011
carol: 1/7/2011
carol: 3/1/2002
mcapotos: 9/17/2001
mcapotos: 8/24/2001
psherman: 5/7/1998
jenny: 4/21/1997
jenny: 4/15/1997
terry: 4/9/1997
terry: 1/10/1997
pfoster: 2/18/1994
carol: 7/12/1993
carol: 8/31/1992
carol: 8/13/1992
carol: 6/23/1992
supermim: 3/16/1992
*RECORD*
*FIELD* NO
138700
*FIELD* TI
*138700 APOLIPOPROTEIN H; APOH
;;GLYCOPROTEIN I, BETA-2; B2GP1;;
GLYCOPROTEIN 1, BETA-2;;
read moreBG
*FIELD* TX
DESCRIPTION
The APOH gene encodes beta-2 glycoprotein I, also known as
apolipoprotein H, a single-chain plasma protein of about 50 kD. Beta-2
GPI binds to and neutralizes negatively charged phospholipid
macromolecules, thereby diminishing inappropriate activation of the
intrinsic blood coagulation cascade. Beta-2 GPI has been implicated in a
variety of physiologic pathways, including blood coagulation,
hemostasis, and the production of antiphospholipid antibodies
characteristic of antiphospholipid syndrome (APS; 107320) (summary by
Mehdi et al., 2003).
CLONING
Lozier et al. (1984) determined the full amino acid sequence of
beta-2-glycoprotein (apoH). The deduced 326-amino acid protein contains
5 attached glucosamine-containing oligosaccharides. Computerized
analysis of the sequence revealed 5 consecutive homologous segments in
which cysteine, proline, and tryptophan appeared to be highly conserved.
Mehdi et al. (1991) cloned and sequenced APOH cDNAs from human liver and
from a human hepatoma cell line. Both cDNAs predicted a protein of 345
amino acids, including a 19-amino acid hydrophobic, N-terminal signal
sequence that is not present in the mature protein. The level of APOH
mRNA expressed by the hepatoma cells was downregulated by incubation
with inflammatory mediators, implying that APOH is a negative
acute-phase protein.
By Northern blot analysis, Steinkasserer et al. (1992) established that
APOH is synthesized in the liver where a transcript of approximately 1.5
kb was identified.
Sanghera et al. (2001) found that the chimpanzee APOH gene encodes a
deduced 326-amino acid protein, as in humans. The human and chimpanzee
APOH proteins share 99.4% sequence similarity.
GENE STRUCTURE
Sheng et al. (1997) found that the mouse Apoh gene contains 8 exons and
spans approximately 18 kb.
Sanghera et al. (2001) found that the chimpanzee APOH gene, like the
human gene, contains 8 exons.
MAPPING
Haagerup et al. (1991) demonstrated RFLPs in the APOH gene and used
these in CEPH family studies to locate the gene on 17q. The marker that
showed closest linkage was HOX2 (142960), located at 17q21-q22; lod
score = 8.83 at theta = 0.05. Linkage to COL1A1 (120150) was indicated
by a lod score of 6.18 at theta = 0.12. By hybridizing a cDNA probe for
APOH to a panel of somatic cell hybrids, Steinkasserer et al. (1992)
showed that the structural locus maps to 17q23-qter.
Nonaka et al. (1992) mapped the mouse Apoh gene to chromosome 11. Nonaka
et al. (1992) commented that the mouse Apoh protein is composed of 5
repeating units called short consensus repeats (SCR), which are found
mostly in the regulatory proteins of the complement system.
GENE FUNCTION
Nakaya et al. (1980) demonstrated beta-2-glycoprotein I activation of
lipoprotein lipase and designated this glycoprotein as apolipoprotein H.
Lozier et al. (1984) noted that B2GI is associated with lipoproteins,
binds to platelets, interacts with heparin, and may be involved in blood
coagulation.
McNeil et al. (1990) identified beta-2-glycoprotein I as a cofactor
required for antiphospholipid antibodies (APA) to bind to cardiolipin.
These findings suggested that APA are directed against a complex antigen
that includes B2GPI. In addition, B2GPI bound to anionic phospholipids
in the absence of anticardiolipin antibodies. McNeil et al. (1990)
hypothesized that anticardiolipin APA may interfere with the function of
apoH in vivo, which may explain the association of these antibodies with
thrombotic tendencies.
Sanghera et al. (1997) noted that apoH had been implicated in a variety
of physiologic pathways including lipoprotein metabolism, coagulation,
and the production of antiphospholipid autoantibodies. They cited
reports supporting the conclusion that apoH is a required cofactor for
anionic phospholipid binding by the antiphospholipid autoantibodies
found in sera of many patients with systemic lupus erythematosus (SLE;
152700) and primary antiphospholipid syndrome (107320), but it does not
seem to be required for the reactivity of antiphospholipid
autoantibodies associated with infections. These studies suggested that
the apoH-phospholipid complex forms the antigen to which the
autoantibodies are directed. Sanghera et al. (1997) postulated that
genetically determined structural abnormalities in the lipid-binding
domain(s) of apoH may affect its ability to bind lipid and consequently
the production of the autoantibodies.
Agar et al. (2010) used electron microscopy to demonstrate that B2GPI
exists in at least 2 different conformations: a closed circular plasma
conformation and an activated open conformation. The closed circular
conformation is maintained by interaction between the first (DI) and
fifth (DV) domains. In the activated open conformation, a cryptic
epitope in the first domain becomes exposed that enables antibodies to
bind and form an antibody-B2GPI complex. The open conformation prolonged
the activated partial thromboplastin time (APTT) when added to normal
plasma, and the APTT was further prolonged by addition of anti-B2GPI
antibodies, consistent with an anticoagulant effect. The conformations
could be converted into each other by changing pH and salt
concentrations.
In a review, Giannakopoulos et al. (2011) noted that B2GPI contains
multiple cysteine residues that mediate platelet and endothelial cell
adhesion via thiol exchange reactions. Evidence also suggests that B2GPI
may play a role in apoptosis by binding to blebs on apoptotic cells.
MOLECULAR GENETICS
Richter and Cleve (1988) demonstrated genetic variation of APOH by means
of isoelectric focusing, and data on gene frequencies of allelic
variants were tabulated by Roychoudhury and Nei (1988).
Using thin-layer polyacrylamide isoelectric focusing gels and
immunologic identification, Kamboh et al. (1988) demonstrated
genetically determined polymorphism of apolipoprotein H. Three common
alleles were identified in U.S. whites and blacks. A fourth allele was
observed in individuals of African descent. Family data confirmed
autosomal codominant inheritance of 4 alleles at a single APOH locus.
Sepehrnia et al. (1988) provided data on the distribution of
apolipoprotein polymorphisms in Nigeria, including polymorphism of APOH.
The observations supported the conclusion that the APOH*4 is a marker
allele unique to blacks and one that may be widely distributed among
African populations, whereas the APOH*1 allele may be a unique Caucasian
allele that was introduced into the black population of the U.S. by
admixture.
Eiberg et al. (1989) reported linkage data suggesting that the
structural and quantitative polymorphisms associated with serum
beta-2-glycoprotein I were very tightly linked (maximum lod score = 3.28
at theta = 0.0, male and female data combined). Sepehrnia et al. (1989)
found specific associations between particular APOH alleles and the
level of triglycerides in females.
In a population of black Africans from the Ivory Coast, Cleve et al.
(1992) found that the gene frequencies of APOH*1, APOH*2, APOH*3, and
APOH*4 were 0.012, 0.921, 0.047, and 0.020, respectively. In a tabular
review of reported frequencies in different populations, APOH*4 was
found only in individuals of African descent. The most common allele in
all populations, including African, Caucasian, European, and East Asian
descent, was APOH*2.
Among 661 non-Hispanic whites, Sanghera et al. (1997) found that the
frequency of the APOH*1, APOH*2, and APOH*3 alleles were 0.059, 0.868,
and 0.073, respectively. Sanghera et al. (1997) determined that the
APOH*1 allele is due to a ser88-to-asn (S88N) substitution in exon 3 of
the APOH gene. The frequency of the asn88 allele was 0.011, 0.043, and
0.056 in blacks, Hispanics, and non-Hispanic whites, respectively. Based
upon reactivity with a certain monoclonal apoH antibody, the APOH*3
allele could be subdivided into APOH*3(W) (reactive) and APOH*3(B)
(non-reactive). The APOH*3(W) allele was found to result from a
trp316-to-ser (W316S) substitution in the APOH gene. White had a
significantly higher frequency of APOH*3(W) (0.059) compared to blacks
(0.008).
Sanghera et al. (1997) found that the W316S substitution in the APOH
gene occurs in the fifth domain (domain V) of the protein, which affects
phospholipid binding. Another structural substitution in this domain,
cys306-to-gly (C306G), was also shown to disrupt binding of APOH to
phospholipid. These data indicated that domain V of APOH harbors the
lipid-binding region.
Among 455 non-Hispanic individuals, Mehdi et al. (1999) found that the
APOH*3(W) allele was associated with decreased plasma levels of apoH and
was estimated to account for about 10% of the phenotypic variation in
plasma levels in both men and women. However, Mehdi et al. (2003) found
that the W316S allele was in linkage disequilibrium with a promoter
polymorphism in the APOH gene, which explained the variation in plasma
apoH levels.
Hirose et al. (1999) found that the val247 allele (138700.0001) was
significantly associated with the presence of anti-B2GPI antibodies in
Asian patients with antiphospholipid syndrome (APS; 107320) in a study
of 370 healthy controls from different racial backgrounds and 149
patients with APS. The V allele and the VV genotype occurred most often
among Caucasians, less among African Americans, and least among Asians.
Conversely, the V allele and the VV genotype were found more frequently
among Asian patients with antiphospholipid syndrome than among controls
(p = 0.0028 and p = 0.0023, respectively). There were no significant
differences in allele or genotype frequencies when comparing Caucasian
or African American APS patients with appropriate controls. The
differences in allele and genotype frequencies seen in Asian APS
patients were restricted to those with anti-B2GPI antibodies.
HISTORY
Haupt et al. (1968) described a family in which 2 brothers had complete
absence of what they termed beta-2-glycoprotein I (Bg) in the serum.
Both parents, a sister, and both children of 1 of the brothers had
half-normal levels of the protein. Cleve and Rittner (1969) found 9
families out of 88 in which 1 parent and about half the children had
intermediate concentrations of beta-2-glycoprotein I, presumed to be
heterozygous for a deficiency ('null') gene.
Hoeg et al. (1985) observed the rare occurrence of total lack of
detectable apoH protein in less than 0.3% of clinic patients. A study of
family members of 5 such patients demonstrated autosomal codominant
inheritance pattern for plasma levels. The authors were impressed by the
lack of consistent effects on other plasma lipoproteins, and concluded
that the lack of apolipoprotein H does not result in a significant
perturbation of normal lipoprotein metabolism, suggesting that the
finding may not have clinical relevance.
Bancsi et al. (1992) concluded that deficiency of plasma B2GPI is not a
risk factor for thrombosis. In a comparison of healthy volunteers and 4
different groups of patients with familial thrombophilia, the prevalence
of B2GPI deficiency (plasma levels less than 77%) was found to be very
similar (6.8-12.5%) and not statistically significant between the
groups. One thrombophilic patient was found to be homozygous-deficient
for B2GPI and this transmission of the defect in his family followed
autosomal inheritance. However, 1 of his brothers was also
homozygous-deficient and was free of thromboembolic complications at the
age of 35 years.
ANIMAL MODEL
Using isoelectric focusing and immunoblotting, Sanghera et al. (2001)
screened 155 chimpanzees (128 unrelated captured parents and 27
captive-born offspring) for the apoH protein polymorphism. The most
common IEF pattern in chimpanzees was identical to a previously
described APOH*3 allele in humans. In addition, they identified in
chimpanzees an allele designated APOH*4, resulting from a lys210-to-glu
missense change in exon 6. They found that the prevalence of anti-apoH
antibodies in chimpanzees (64%) was unusually high compared to that in
humans. No association was found between the lys210-to-glu mutation and
the occurrence of anti-apoH antibodies. The authors suggested that the
chimpanzee may serve as a useful animal model for human antiphospholipid
syndrome (107320).
Sheng et al. (2001) found that B2ghi-null mice were born at lower than
expected frequencies, suggesting that B2gpi may play a role in
implantation. However, B2gpi-null mice themselves did not show
reproductive abnormalities: the number of pregnancies, litter size, and
birth weight was similar to that of heterozygotes and controls.
B2gpi-null mice had no detectable organ pathology, and in vivo
coagulation profiles were also similar to controls. However, in vitro
studies of blood derived from the B2gpi-null mice showed less thrombin
generation compared to heterozygotes or controls.
*FIELD* AV
.0001
APOH POLYMORPHISM
APOH, VAL247LEU
Steinkasserer et al. (1993) described a 2-allele RsaI restriction
fragment length polymorphism (RFLP) in the APOH gene and demonstrated
that it led to a val247-to-leu (V247L) substitution. In studies of 34
unrelated parents in the CEPH family panel, allele frequencies were
found to be 0.76 for valine and 0.23 for leucine. The val-leu
polymorphism did not correlate with the 4 isoelectric focusing alleles
previously described.
*FIELD* SA
Cleve (1968); Eiberg et al. (1984); Koppe et al. (1970); Rahimi et
al. (1977); Walter et al. (1979)
*FIELD* RF
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*FIELD* CN
Cassandra L. Kniffin - updated: 6/13/2011
Cassandra L. Kniffin - updated: 1/14/2011
Rebekah S. Rasooly - updated: 5/7/1998
Victor A. McKusick - updated: 4/21/1997
Victor A. McKusick - updated: 4/15/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 06/24/2011
ckniffin: 6/13/2011
terry: 2/18/2011
carol: 1/24/2011
ckniffin: 1/14/2011
carol: 1/7/2011
carol: 3/1/2002
mcapotos: 9/17/2001
mcapotos: 8/24/2001
psherman: 5/7/1998
jenny: 4/21/1997
jenny: 4/15/1997
terry: 4/9/1997
terry: 1/10/1997
pfoster: 2/18/1994
carol: 7/12/1993
carol: 8/31/1992
carol: 8/13/1992
carol: 6/23/1992
supermim: 3/16/1992