Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myosin-binding-protein C (MyBP-C) is a myosin-associated protein of unknown function found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. Using a cDNA clone encoding the fast-type isoform of chicken MyBP-C, we screened a human fetal muscle cDNA library and isolated clones encoding the full-length human fast-type isoform of MyBP-C. cDNA clones encoding the slow-type isoform of human MyBP-C, were also isolated and fully sequenced. Northern-blot analysis demonstrated skeletal muscle-specific expression of these gene products. Using human/hamster somatic-cell hybrids, we were able to map the slow-type MyBP-C to human chromosome 12, and the fast-type MyBP-C to chromosome 19. The cDNA for human fast-type MyBP-C encodes a polypeptide of 1142 amino acids with an expected molecular mass of 128.1 kDa. Comparison of this cDNA with other members of the MyBP family reveals extensive primary-sequence conservation. Each MyBP-C contains seven immunoglobulin C2 motifs and three fibronectin type-III repeats in the arrangement C2-C2-C2-C2-C2-III-III-C2-III-C2. Regions of high identity shared by the chicken and the two human proteins are not restricted to the immunoglobulin and fibronectin motifs. Sequence comparison of all three proteins has allowed us to map a highly conserved region between the first and second C2 motifs, the only large spacer sequence present between motifs in these proteins.
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PMID:Complete sequence of human fast-type and slow-type muscle myosin-binding-protein C (MyBP-C). Differential expression, conserved domain structure and chromosome assignment. 837

Thromboembolism is a prominent but poorly understood feature of eosinophilic, or Loeffler's endocarditis. Eosinophil (EO) specific granule proteins, in particular major basic protein (MBP), accumulate on endocardial surfaces in the course of this disease. We hypothesized that these unusually cationic proteins promote thrombosis by binding to the anionic endothelial protein thrombomodulin (TM) and impairing its anticoagulant activities. We find that MBP potently (IC50 of 1-2 microM) inhibits the capacity of endothelial cell surface TM to generate the natural anticoagulant activated protein C (APC). MBP also inhibits APC generation by purified soluble rabbit TM with an IC50 of 100 nM without altering its apparent Kd for thrombin or Km for protein C. This inhibition is reversed by polyanions such as chondroitin sulfate E and heparin. A TM polypeptide fragment comprising the extracellular domain that includes its naturally occurring anionic glycosaminoglycan (GAG) moiety (TMD-105) is strongly inhibited by MBP, whereas its counterpart lacking the GAG moiety (TMD-75) is not. MBP also curtails the capacity of TMD-105 but not TMD-75 to prolong the thrombin clotting time. Thus, EO cationic proteins potently inhibit anticoagulant activities of the glycosylated form of TM, thereby suggesting a potential mechanism for thromboembolism in hypereosinophilic heart disease.
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PMID:Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease. 838 94

Human breast and pancreatic adenocarcinomas are tumors of ductal epithelial cell origin and as such produce and express on their surface polymorphic epithelial cell mucin encoded by the MUC 1 gene. We have previously reported that tumor-specific cytotoxic T cells derived from patients bearing such tumors recognize specific epitopes on the mucin polypeptide core. This recognition was not MHC-restricted because of the highly repetitive sequence of the polypeptide core, which allows simultaneous recognition of many identical epitopes, and cross-linking and aggregation of TCR on mucin-specific T cells. Those studies were performed with limited numbers of tumor cells or allogeneic tumor cell lines. A renewable source of autologous cells presenting this Ag was necessary to further explore mucin-specific immunity. We report here successful establishment and functional analysis of mucin-specific CTL lines and clones derived from breast and pancreatic cancer patients, using either autologous or allogeneic mucin-transfected B cells as Ag. Our results demonstrate that transfection of autologous or allogeneic B cells with mucin confers upon them tumor Ag-presenting ability as well as susceptibility to lysis by mucin-specific CTL. Transfection of APC with this or any other human tumor Ag that may be molecularly defined in the future provides a unique and powerful tool with which to examine the ability of a tumor-associated Ag to stimulate T cell responses.
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PMID:Tumor-specific cytotoxic T cell clones from patients with breast and pancreatic adenocarcinoma recognize EBV-immortalized B cells transfected with polymorphic epithelial mucin complementary DNA. 839 50

A new thrombin inhibitor, bothrojaracin, has been identified and purified to homogeneity from the venom of Bothrops jararaca, the most common venomous snake of South America. Bothrojaracin has an isoelectric point of 4.2 and a molecular mass of 27 kDa and is made of two distinct polypeptide chains of 15 and 13 kDa, linked by disulfide bridges. Purified bothrojaracin is devoid of phospholipase A2, amidolytic, or fibrino (geno)lytic activity. Bothrojaracin forms a noncovalent complex with alpha-thrombin, without changing its catalytic activity on small peptide substrates. Bothrojaracin behaves as a potent and specific antagonist of thrombin-induced platelet aggregation and secretion, characterized by an IC50 ranging from 1 to 20 nM depending on the alpha-thrombin concentration. Bothrojaracin prolongs fibrinogen clotting time, and this effect is related to a competitive inhibition of the binding of alpha-thrombin to fibrin(ogen) (Ki 15 nM). Binding of alpha-thrombin to thrombomodulin is inhibited up to 87% by bothrojaracin, and the rate of protein C activation by alpha-thrombin is also decreased. Bothrojaracin antagonizes the inhibition of thrombin amidolytic activity by hirudin. These results indicate that bothrojaracin acts as a very potent ligand of the exosite of alpha-thrombin.
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PMID:Bothrojaracin, a new thrombin inhibitor isolated from Bothrops jararaca venom: characterization and mechanism of thrombin inhibition. 839 28

Recently isolated escape mutants of human respiratory syncytial virus (HRSV) are described. The mutants were selected after serial passage of the Long strain in the presence of monoclonal antibodies directed against the attachment (G) glycoprotein. The genetic changes associated to the mutant phenotype were nucleotide substitutions leading to either amino acid replacements or new stop codons that shorten the G polypeptide by one amino acid. Sequence changes within the three C-terminal residues of the G molecule abolished multiple epitopes, some of them being distinguished only by virus-binding inhibition of the corresponding antibodies with a panel of antiidiotypic antisera. These results extend previous studies that demonstrated the extreme capacity of HRSV to accommodate multiple sequence changes within the antigenically relevant G protein C-terminal third. These results are discussed in terms of both the antigenic structure of the G molecule and the generation of new antigenic variants that mimic natural variants of HRSV.
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PMID:The three C-terminal residues of human respiratory syncytial virus G glycoprotein (Long strain) are essential for integrity of multiple epitopes distinguishable by antiidiotypic antibodies. 854 3

The mutations observed in patients with antithrombin and protein C deficiencies are mostly substitutions of one nucleotide, or deletions/insertions of fewer than 10 nucleotides in the exons and intron-exon junctions. These genomic abnormalities result in missense changes (involving aminoacids important for protein folding), aberrant polypeptide chains and/or premature termination codons, or abnormal splicing precluding DNA transcription. The number of mutations so far identified is such that it is difficult to use genomic DNA analysis for diagnostic purpose. However, identification of the gene defect can be useful in well-defined situations, such as the risk of homozygosity, and complex or ambiguous plasma phenotypes, which frequently occur in protein C deficiency. Protein S deficiency, the molecular bases of which have been less extensively studied, is due to micromodifications of the coding sequence in only half the cases investigated so far. The mechanisms involved in the remaining cases remain to be identified.
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PMID:A review of mutations causing deficiencies of antithrombin, protein C and protein S. 857 31

Protein C (OprC) of the outer membrane of Pseudomonas aeruginosa forms small channels, as assayed by the liposome swelling method. We report here that OprC functions as a channel-forming and copper-binding protein. OprC purified to homogeneity formed a channel in planar lipid bilayers with an ion conductance of about 200 pS in 1 M NaCl. Cloning and sequencing of the gene encoding OprC revealed that it specified a polypeptide comprising 723 and 668 amino acid residues for the precursor and mature polypeptides (M(r) 73,372), respectively. The amino acid sequence of OprC showed the highest degree of similarity with that of NosA of Pseudomonas stutzeri (65% sequence identity) which conveys Cu2+ to intracellular acceptor(s). OprC showed high copper-binding activity (Kd = 2.6 microM) in aqueous solution containing surfactant. The expression of OprC appeared to be repressed by exogenous Cu2+ and derepressed by anaerobiosis in the presence of nitrate. These results suggest that OprC might be involved in copper utilization.
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PMID:Protein C (OprC) of the outer membrane of Pseudomonas aeruginosa is a copper-regulated channel protein. 876 Sep 27

Great progress has been made within the past 10 years in characterizing, assaying, and describing mechanism(s) of action in vitro of antiphospholipid antibodies (a-PL Abs); three prominent members are reagin, anticardiolipin antibodies (a-CL Abs), and the lupus anticoagulants (LAC). The major focus of this review is on basic and current biochemical and immunologic research. First, the biochemistry, structural composition, and sources of anionic and dipolar ionic (zwitterionic) phospholipids are discussed together with several serum antibodies directed to these phospholipids. Cardiolipin, the most acidic phospholipid (net negative charge of 2 at pH 7.0) has been historically important as an antigen for testing reagin in syphilis serology, and currently is part of the antigenic composition used in the Venereal Disease Research Laboratory (VDRL) tests. In this connection, the chronic biological false-positive test for syphilis and the LAC are discussed in association with autoimmune disorders such as systemic lupus erythematosus. Second, a naturally occurring plasma anticoagulant in vitro and a critical cofactor for binding of purified autoimmune a-CL Abs to cardiolipin is considered, the beta 2-glycoprotein I (beta 2-gpI). This single-chain plasma polypeptide is highly glycosylated, has 326 amino acids, a molecular weight of 50 kD, and is characterized by repeating amino acid motifs or domains that structurally resemble multiple loops. The highly cationic C-terminal fifth domain binds to anionic phospholipids. The beta 2-gpI is a member of the short consensus repeat superfamily of proteins, and is compared with other proteins with similar domains. Third, experiments are detailed for defining LAC and distinguishing it from other a-CL Abs. Cofactors are also associated with LAC and include beta 2-gpI, prothrombin, protein C, protein S, tissue factor, and factor XI. Thus, LAC antibodies are heterogeneous, and no individual assay can detect all LACs. Because patients with syphilis and other infectious diseases have no cofactor associated with a-CL Abs, their plasma LACs are negative. The a-CL Abs found in infection are not associated with the clinical features of the antiphospholipid syndrome. LAC assays are important because of the pathogenetic association with clinical observations of venous and arterial thrombosis, thrombocytopenia, and recurrent fetal loss. Finally, reports leading to development of currently used direct solid-phase enzyme-linked immunosorbent assays (ELISA) for testing a-PL Abs are outlined; these developments have greatly increased understanding of the basic immunology of target antigens and their respective antibodies. Of significance, a-CL Abs cross-react with other anionic phospholipids. Additionally, the results of these assays led to the realization that high levels of circulating a-PL Abs over long periods are associated with a number of clinical problems now known collectively as the antiphospholipid syndrome.
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PMID:Antiphospholipid antibodies: basic immunology and assays. 914 49

Defects in the APC gene are inarguably linked to the progression of colon cancers that arise both sporadically and through the transmission of germline mutations. Genetic evidence from humans and mouse models suggest that APC is a classic tumor suppressor in that both alleles likely require inactivation for tumor growth to ensue. Nearly all of the mutations, germline and somatic, result in premature termination of the single polypeptide chain, normally consisting of 2843 amino acids. Several definable motifs have now been mapped to the linear amino acid sequence of the APC polypeptide. These include an oligomerization domain, armadillo repeats, binding sites for beta-catenin, the human discs large protein, microtubules, and other proteins of unknown function. Inactivation of APC in cancer is likely due to loss of function(s) normally associated with the deleted protein structure.
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PMID:The adenomatous polyposis coli (APC) tumor suppressor. 919 22

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy. The gene for FA complementation group A (FAA) recently has been cloned. The cDNA is predicted to encode a polypeptide of 1,455 amino acids, with no homologies to any known protein that might suggest a function for FAA. We have used single-strand conformational polymorphism analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants are probably benign polymorphisms, of which nine are common and can be used for various applications, including mapping studies for other genes in this region of chromosome 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants are likely to be pathogenic mutations. Seventeen of these are microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the International Fanconi Anemia Registry for two of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. 3788-3790del appears in a variety of ethnic groups and is found on at least two different haplotypes. We suggest that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germ-line and somatic mutations in a variety of cancer-related genes, including p53, APC, RB1, WT1, and BRCA1, may be a major mechanism for FAA mutagenesis.
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PMID:Sequence variation in the Fanconi anemia gene FAA. 937 98


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