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

We have investigated the ability of APC Class II molecules to bind and release exogenous peptides, two phenomena that are still poorly understood. In order to investigate the half-life of the complex of an exogenous peptide with DR molecules we have evaluated the uptake and release of the radiolabeled peptide 17-29-Tyr of influenza virus matrix protein (MA 17-29-Y) by a B-EBV cell line at different times and under different conditions. We have found that the kinetics of both binding and release of the peptide are very fast in living cells; using glutaraldehyde-fixed cells, the kinetics of the two phenomena are slow, closely resembling those observed with the same peptide and purified, immobilized DR molecules. As confirmed by the study of a specific T-cell clone activation, the Class II-MA 17-29-Y complexes are short-living ones, with an average half-life of 55 min, and the DR molecules that bind exogenous peptides continuously undergo peptidic exchange. These data, taken together, suggest that the APC are endowed with cellular mechanisms that increase the efficiency of both the loading and the unloading of Class II HLA with exogenous peptides. These mechanisms do not appear to require ATP or to involve newly synthesized Class II molecules, intracellular acidic compartments, or the microtubule-microfilament system. On the other hand, an undamaged cell membrane appears to be crucial for an efficient binding.
 ...
PMID:Cellular mechanisms of exogenous peptide binding to HLA class II molecules in B cells. 816 38

The natural Ag influenza virus A was used to test the requirements for the HLA-DR1-restricted presentation of the epitopes 18-29 in the matrix protein and 307-318 in the hemagglutinin protein. CD4+ cytotoxic T cell clones of similar efficiency were used to detect presentation of these two epitopes. Presentation of the matrix epitope by APC pulsed with either inactivated virus particles or purified soluble protein followed the classical pathway in that 1) it required invariant chain expression, 2) it was blocked by inhibition of protein synthesis, and 3) it was dependent on a function(s) encoded in the MHC class II region. These characteristics suggest that peptides corresponding to the matrix epitope can only load onto newly synthesized class II molecules that were targeted to a processing compartment by the invariant chain. In contrast, presentation of the hemagglutinin epitope processed from virus particles followed a different pathway. First, presentation of hemagglutinin was independent of invariant chain expression. Second, a human B lymphoblastoid cell line in which protein synthesis was inhibited for 9 h was still able to present hemagglutinin even at very low doses of Ag. Third, a DR1-transfected mutant B cell line missing the MHC class II region was able to present hemagglutinin. Thus, mature class II alpha beta molecules can acquire immunogenic peptides derived from intact natural Ags for presentation to CD4+ T cells. This pathway may be useful for the binding of peptides derived from Ags that are rapidly degraded upon uptake into APC.
 ...
PMID:Two processing pathways for the MHC class II-restricted presentation of exogenous influenza virus antigen. 817 8

The nuclear matrix appears to play an important role in developmental gene expression during osteoblast differentiation. To better understand this role, we examined nuclear matrix DNA-binding proteins that are sequence-specific and interact with the osteocalcin gene promoter. Multiple protein-DNA interactions involving two distinct nuclear matrix proteins occur within the 5' regulatory sequences (nt -640 to -430). One of these proteins, NMP-1, is a ubiquitous, cell growth-regulated protein that is related to the transcription factor ATF and resides in both the nuclear matrix and the nonmatrix nuclear compartment. The other protein, NMP-2, is a cell type-specific, 38-kDa promoter factor that recognizes binding sites resembling the consensus site for the CCAAT/enhancer-binding protein C/EBP and is localized exclusively on the nuclear matrix. NMP-1 and NMP-2 each interact with two nuclear matrix protein-binding elements. These elements are present near key regulatory sites of the osteocalcin gene promoter, such as the principal steroid hormone (vitamin D)-responsive sequences. Binding in this region of the osteocalcin gene promoter suggests transient associations with the nuclear matrix that are distinct from the stable interactions of matrix attachment regions. Our results are consistent with involvement of the nuclear matrix in concentrating and/or localizing transcription factors that mediate the basal and steroid hormone responsiveness of osteocalcin gene transcription.
 ...
PMID:Osteocalcin gene promoter-binding factors are tissue-specific nuclear matrix components. 847 55

Coumarin derivatives and anticonvulsants administered during pregnancy enter the fetal circulation, interfering with the action of vitamin K. Vitamin K plays a crucial part in the gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors prothrombin, FVII, FIX, and FX. Other vitamin K-dependent proteins in the coagulation cascade are protein C and protein S. Vitamin K-dependent bone proteins are osteocalcin and gamma-carboxyglutamate matrix protein. Administration of coumarol derivatives results in under carboxylation of the vitamin K-dependent proteins. Anticoagulation therapy with warfarin is followed by an increased risk of embryopathy, which has been shown to be greatest between gestational weeks 6 and 12. Administration of warfarin is also followed by an increased risk both of fetal intraventricular hemorrhage, and of cerebral microbleedings, which may result in microencephaly and mental retardation. Treatment with coumarol derivatives should therefore be avoided during pregnancy, even in pregnant women with artificial heart valves, and replaced by heparin. Hemorrhage in the newborn related to the use of anticonvulsant drugs during pregnancy occurs very early within the first 24 hours, probably due to increased degradation of vitamin K. Transplacental administration of vitamin K has been shown to prevent neonatal hemorrhage induced by maternal anticonvulsant therapy. Prophylactic administration of vitamin K, especially by intramuscular injection, has been reported to be associated with an increased risk of childhood cancer. However, subsequent extensive studies have yielded no evidence of any relationship between prophylactic vitamin K administration and the occurrence of childhood cancer.
 ...
PMID:Antenatal drugs affecting vitamin K status of the fetus and the newborn. 874 99

Vitamin K is a cofactor for the synthesis of blood coagulation Factors II, VII, IX and X, and inhibitors such as Protein C and S and bone matrix protein. Its active form is a coenzyme in the glutamic acid carboxylation. Vitamin K-dependent factors form enzymatic complexes with calcium and membrane phospholipids. The insufficiency of gamma glutamic carboxylation impairs the hemostatic function. Hereditary deficiencies, antibiotics and oral anticoagulants, decrease the capacity of complex formation giving way to hemorrhage or thrombosis, or bone mass disturbances which are easily treated with administration of Vitamin K. The main causes of Vitamin K deficiency are lack of hepatic storage in newborns, liver insufficiency, malabsorption, dietetic deficiency, therapy with the antibiotics and coumarin administration. For the study of Vitamin K there are methods to measure the Vit K dependent proteins and as well methods to measure specifically the quinonas.
 ...
PMID:[Vitamin K: biochemistry, function, and deficiency. Review]. 978 May 55

Arterial and venous thrombosis are a major cause of morbidity and mortality. Anticoagulants are a cornerstone of treatment in patients with these disorders. The two most frequently used anticoagulants, heparin and warfarin, have pharmacological and/or biophysical limitations that make them difficult to use in day-to-day clinical practice. Development of new anticoagulants, which were designed to overcome these limitations, has been facilitated by an increased understanding of the coagulation cascade, the advent of molecular modeling and structure-based drug design, and the realization that the treatment of thrombosis and its complications consumes billions of dollars in annual healthcare expenditures. New anticoagulants target various steps in the coagulation pathway. Coagulation is triggered by the factor VIIa/tissue factor complex and propagated by factors Xa and IXa, together with their activated cofactors, factor Va and VIIIa, respectively. Thrombin, the final effector in coagulation, then converts soluble fibrinogen into insoluble fibrin, the major matrix protein of the clot. New anticoagulation drugs that target each of these clotting enzymes have been developed. This review will focus on those drugs in more advanced stages of clinical evaluation. These include inhibitors of initiation of coagulation (tissue factor pathway inhibitor, nematode anticoagulant peptide and active-site blocked factor VIIa), inhibitors of propagation of coagulation (active-site blocked factor IXa, antibodies against factor IX/IXa, fondaparinux sodium, direct factor Xa inhibitors, protein C derivatives and soluble thrombomodulin), and thrombin inhibitors (hirudin, bivalirudin, argatroban and ximelagatran).
 ...
PMID:New anticoagulants: current status and future potential. 1472 32

For many enveloped viruses, cellular multivesicular body (MVB) sorting machinery has been reported to be utilized for efficient viral budding. Matrix and Gag proteins have been shown to contain one or two L-domain motifs (PPxY, PT/SAP, YPDL, and FPIV), some of which interact specifically with host cellular proteins involved in MVB sorting, which are recruited to the viral budding site. However, for many enveloped viruses, L-domain motifs have not yet been identified and the involvement of MVB sorting machinery in viral budding is still unknown. Here we show that both Sendai virus (SeV) matrix protein M and accessory protein C contribute to virus budding by physically interacting with Alix/AIP1. A YLDL sequence within the M protein showed L-domain activity, and its specific interaction with the N terminus of Alix/AIP1(1-211) was important for the budding of virus-like particles (VLPs) of M protein. In addition, M-VLP budding was inhibited by the overexpression of some deletion mutant forms of Alix/AIP1 and depletion of endogenous Alix/AIP1 with specific small interfering RNAs. The YLDL sequence was not replaceable by other L-domain motifs, such as PPxY and PT/SAP, and even YPxL. C protein was also able to physically interact with the N terminus of Alix/AIP1(212-357) and enhanced M-VLP budding independently of M-Alix/AIP1 interaction, although it was not released from the transfected cells itself. Our results suggest that the interaction of multiple viral proteins with Alix/AIP1 may enhance the efficiency of the utilization of cellular MVB sorting machinery for efficient SeV budding.
 ...
PMID:The YLDL sequence within Sendai virus M protein is critical for budding of virus-like particles and interacts with Alix/AIP1 independently of C protein. 1716 5

Paramyxoviruses are negative-sense single-stranded RNA viruses that comprise many important human and animal pathogens, including human parainfluenza viruses. These viruses bud from the plasma membrane of infected cells after the viral ribonucleoprotein complex (vRNP) is transported from the cytoplasm to the cell membrane via Rab11a-marked recycling endosomes. The viral proteins that are critical for mediating this important initial step in viral assembly are unknown. Here, we used the model paramyxovirus, murine parainfluenza virus 1, or Sendai virus (SeV), to investigate the roles of viral proteins in Rab11a-driven virion assembly. We previously reported that infection with SeV containing high levels of copy-back defective viral genomes (DVGs) (DVG-high SeV) generates heterogenous populations of cells. Cells enriched in full-length (FL) virus produce viral particles containing standard or defective viral genomes, while cells enriched in DVGs do not, despite high levels of defective viral genome replication. Here, we took advantage of this heterogenous cell phenotype to identify proteins that mediate interaction of vRNPs with Rab11a. We examined the roles of matrix protein and nucleoprotein and determined that their presence is not sufficient to drive interaction of vRNPs with recycling endosomes. Using a combination of mass spectrometry and comparative analyses of protein abundance and localization in DVG-high and FL-virus-high (FL-high) cells, we identified viral polymerase complex component protein L and, specifically, its cofactor C as interactors with Rab11a. We found that accumulation of L and C proteins within the cell is the defining feature that differentiates cells that proceed to viral egress from cells containing viruses that remain in replication phases.IMPORTANCE Paramyxoviruses are members of a family of viruses that include a number of pathogens imposing significant burdens on human health. In particular, human parainfluenza viruses are an important cause of pneumonia and bronchiolitis in children for which there are no vaccines or directly acting antivirals. These cytoplasmic replicating viruses bud from the plasma membrane and co-opt cellular endosomal recycling pathways to traffic viral ribonucleoprotein complexes from the cytoplasm to the membrane of infected cells. The viral proteins required for viral engagement with the recycling endosome pathway are still not known. Here, we used the model paramyxovirus Sendai virus, or murine parainfluenza virus 1, to investigate the role of viral proteins in this initial step of viral assembly. We found that the viral polymerase components large protein L and accessory protein C are necessary for engagement with recycling endosomes. These findings are important in identifying viral proteins as potential targets for development of antivirals.
 ...
PMID:The Viral Polymerase Complex Mediates the Interaction of Viral Ribonucleoprotein Complexes with Recycling Endosomes during Sendai Virus Assembly. 3284 50