Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02749 (beta2-glycoprotein I)
 836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human apolipoprotein H (ApoH), also called beta 2-glycoprotein I, is a 50-kDa serum glycoprotein whose function is not clearly defined. We have cloned and sequenced ApoH cDNAs both from human liver and from a human hepatoma cell line (HepG2). Both cDNA sequences predict a protein 345 amino acids (aa) in length. This sequence includes a 19-aa hydrophobic, N-terminal signal sequence which is not present in the mature protein [Lozier et al., Proc. Natl. Acad. Sci. USA 81 (1984) 3640-3644]. It differs from this previously reported aa sequence at two positions, both of which strengthen the conservation among the four short consensus repeats within the ApoH molecule. COS-1 cells transiently transfected with the ApoH cDNA in a eukaryotic expression vector produced a single species of ApoH mRNA and secreted in the ApoH protein. The level of ApoH mRNA expressed by HepG2 cells is downregulated by incubation with inflammatory mediators, implying that ApoH is a negative acute-phase protein.
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PMID:Nucleotide sequence and expression of the human gene encoding apolipoprotein H (beta 2-glycoprotein I). 174 14

Lipoprotein(a) [Lp(a)], which has been shown to interact with fibrin(ogen) and other components of the blood clotting cascade, is a major independent risk factor for atherothrombotic disease in humans. The physiological function(s) of Lp(a), as well as the precise mechanism(s) by which high plasma levels of Lp(a) increase risk are unknown. Identification of further potential apo(a)-protein ligands may be crucial to illuminate apo(a)'s function(s) and pathophysiological properties. We used the repetitive apo(a) kringle IV type 2, which is variable in number in apo(a), to screen a human liver cDNA library by the yeast two-hybrid interaction trap system. Among 11 positive clones that emerged from the screen, eight clones were identified as beta-2 glycoprotein I and one as fibronectin. Coimmunoprecipitation experiments confirmed that beta-2 glycoprotein I and apo(a)/Lp(a) interact in human plasma and in cell culture supernatants of COS-1 cells, which ectopically expressed apo(a). The apo(a)-beta2-glycoprotein I interaction indicates new potential roles for Lp(a) in fibrinolysis and autoimmunity.
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PMID:Novel interaction of apolipoprotein(a) with beta-2 glycoprotein I mediated by the kringle IV domain. 926 65

Apolipoprotein H (apoH; also known as beta2-glycoprotein I), is an essential cofactor for the binding of certain antiphospholipid antibodies (APA) to anionic phospholipid. The gene coding for apoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect the binding of apoH to anionic phospholipids and consequently the production of APA. Our group has identified two common mutations at codons 306 (Cys-->Gly) and 316 (Trp-->Ser) in the fifth domain of apoH which affect the binding of apoH to anionic phospholipids (phosphatidylserine or cardiolipin). ApoH from serum samples homozygous for each of these mutations or compound heterozygotes for both mutations showed no binding with anionic phospholipids on ELISA. In vitro mutagenesis and transient expression of these mutations in COS-1 cells followed by cardiolipin binding studies confirmed that Gly306 and Ser316 are causative mutations. Our data indicate that the fifth domain of apoH is essential for anionic phospholipid binding and genetically determined variation in this domain can affect the production of apoH-dependent APA.
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PMID:Genetics of apolipoprotein H (beta2-glycoprotein I) and anionic phospholipid binding. 981 64

Apolipoprotein H (apoH, protein; APOH, gene) binds to negatively charged phospholipids, which triggers the production of a subset of autoantibodies against phospholipid in patients with autoimmune diseases. We have demonstrated that two naturally occurring missense mutations in the fifth domain of apoH, Trp316Ser and Cys306Gly, disrupt the binding of native apoH to phosphatidylserine [Sanghera, D. K., Wagenknecht, D. R., McIntyre, J. A. & Kamboh, M. I. (1997) Hum. Mol. Genet. 6, 311-316]. To confirm whether these are functional mutations, we mutagenized APOH cDNAs and transiently expressed them in COS-1 cells. The cardiolipin ELISA of wild-type and mutant recombinant apoH confirmed that the Gly306 and Ser316 mutations are responsible for abolishing the binding of recombinant apoH to cardiolipin. These mutations, however, had no effect on the levels of expression or secretion of recombinant apoH in transfected COS-1 cells. While the Cys306Gly mutation disrupts a disulfide bond between Cys306 and Cys281, which appears to be critical for clustering positively charged amino acids, the Trp316Ser mutation affects the integrity of an evolutionarily conserved hydrophobic sequence at position 313-316 (Leu-Ala-Phe-Trp), which is hypothesized to interact with anionic phospholipid. To test this hypothesis, we exchanged the remaining three hydrophobic amino acids with neutral amino acids by site-directed mutagenesis (Leu313Gly, Ala314Ser and Phe315Ser). Binding of the Leu313Gly and Phe315Ser mutants to cardiolipin was significantly reduced to 25% and 13%, respectively, of that of the wild-type. On the other hand, the Ala314Ser mutation showed normal cardiolipin binding. Taken together with our previous findings, these results strongly suggest that the configuration of the fifth domain of apoH, as well as the integrity of the highly conserved hydrophobic amino acids at positions 313-316, is essential for the binding of apoH to anionic phospholipid.
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PMID:A hydrophobic sequence at position 313-316 (Leu-Ala-Phe-Trp) in the fifth domain of apolipoprotein H (beta2-glycoprotein I) is crucial for cardiolipin binding. 1071 9

Apolipoprotein H (APOH), also known as beta2-glycoprotein I, is a major autoantigen for the production of antiphospholipid antibodies (APA) in autoimmune diseases. APA is also recognized by a cryptic epitope generated following the interaction of APOH with anionic phospholipids (PL). The prevalence of APA in the general U.S. white population is about 10%, but it ranges from 30-70% in patients with lupus and antiphospholipid syndrome. Since the structural characterization of APOH from different mammalian species is important to identify the evolutionary conserved regions that may be critical for its function, we have previously determined the chimpanzee APOH gene structure and the prevalence of APA. There are only two amino acid differences between the chimpanzee and human wild type APOH proteins. Chimpanzees have an unusually high prevalence (64%) of APA. There is a common protein polymorphism in the human APOH gene, with the occurrence of four alleles APOH*1, APOH*2, APOH*3 and APOH*4, the latter being present only in blacks. Based on its differential reactivity with an APOH monoclonal antibody, the APOH*3 allele is further divided into APOH*3(W) (present only in whites) and APOH*3(B) (present only in blacks). In this study we have screened a large African population (n = 755) to determine the prevalence of APA and the molecular basis of the protein polymorphism. Almost 50% of the Africans were found to be positive for APA. The APOH*3(B) allele was found to be identical to the chimpanzee's wild type APOH. Novel two-site or three-site haplotypes, encoded in the third domain of APOH, explained the molecular basis of the APOH*3(B), APOH*3(W) and APOH*4 alleles. Based on the comparison of the human and chimpanzee APOH DNA sequences, we suggest that the APOH*3(W) and APOH*4 alleles arose on the ancestral APOH*3(B) haplotype after the split of human races. We also found that these haplotypes are associated with the occurrence of APA. Recombinant APOH haplotypes, expressed in COS-1 cells, showed that these mutations also affect the binding of APOH to anionic PL.
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PMID:Single nucleotide polymorphisms in the coding region of the apolipoprotein H (beta2-glycoprotein I) gene and their correlation with the protein polymorphism, anti-beta2glycoprotein I antibodies and cardiolipin binding: description of novel haplotypes and their evolution. 1522 55

This study characterized the human apolipoprotein H [APOH; beta(2)-glycoprotein I (beta(2)GPI)] promoter and its variants by in vitro functional experiments and investigated their relationship with human plasma beta(2)GPI levels. We examined the individual effects of 12 APOH promoter single nucleotide polymorphisms in the 5' flanking region of APOH (approximately 1.4 kb) on luciferase activity in COS-1 cells and HepG2 cells and their impact on plasma beta(2)GPI levels in 799 American White people, the DNA binding properties of the APOH promoter using an electrophoretic mobility shift assay in HepG2 cells, the effects of serial deletion analysis of the APOH 5' flanking region in COS-1 and HepG2 cells and cross-species conservation of the APOH promoter sequence. The variant alleles of three single nucleotide polymorphisms (-1219G>A, -643T>C and -32C>A) showed significantly lower luciferase expression (51, 40 and 37%, respectively) as compared with the wild-type allele. The electrophoretic mobility shift assay demonstrated that these three variants specifically bind with protein(s) from HepG2 cell nuclear extracts. Three-site haplotype analysis (-1219G>A, -643T>C and -32C>A) revealed one haplotype carrying -32A (allele frequency = 0.075) to be significantly associated with decreased plasma beta(2)GPI levels (P < 0.001). Deletion analysis localized the core APOH promoter to approximately 160 bp upstream of ATG codon with the presence of critical cis-acting elements between -166 and -65. Cross-species conservation analysis of the APOH promoters of seven species indicated that basic promoter elements are highly conserved across species. In conclusion, we have characterized the functional promoter of APOH and identified functional variants that affect the transcriptional activity of the APOH promoter.
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PMID:Functional and genetic characterization of the promoter region of apolipoprotein H (beta2-glycoprotein I). 2008 41