Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human gametes and pre-implantation embryos express selectively several complement regulatory proteins. Membrane cofactor protein (MCP, CD46) and decay accelerating factor (DAF, CD55) are regulators for C3 convertases and protectin (CD59) is an inhibitor of the membrane attack complex. These three proteins were identified on human sperm and found to be functional. CD55 and CD59 were both expressed by the plasmic membrane of unfertilized oocytes and pre-implantation embryos. CD46 was not present on unfertilized oocytes but appeared at the 6/8 cell-stage embryo when human gene expression first occurs. Complement receptor 1 (CR1, CD35) and MHC class I antigens were not found on oocytes neither on embryos. Such a selective expression of complement regulatory proteins associated with the lack of MHC class I antigens may represent an immune protective mechanism by which human gametes and pre-implantation embryos escape from complement-mediated damage during their travel through the female genital tract. Indeed uterine, tubal and follicular fluids contain all the components of the complement cascade, including classical and alternative pathways. Nevertheless participation of CD46 and CD59 in cell to cell interaction during fertilization and/or implantation cannot be excluded. CD59 is an adhesive molecule involved in the rosette phenomena and CD46 has been described as the human receptor for measles virus, which binds through a fusion protein. Monoclonal antibodies raised against these two proteins (CD46 and CD59) are able to inhibit heterospecific fertilization between zona-free hamster oocytes and human spermatozoa suggesting the role of these proteins during fertilization.
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PMID:[Expression and role of complement regulatory proteins on human gametes and pre-implantation embryos]. 749 32

Human membrane cofactor protein (MCP, CD46) functions as an inhibitor of the complement (C) cascade to protect host cells from C attack, and as a receptor for measles virus (MV). Normal human sera contains 10-60 ng/ml of naturally produced soluble forms of MCP, which is also a cofactor for the factor I-mediated inactivation of C3b. We produced monoclonal antibodies (mAb) against MCP and a recombinant soluble form of MCP similar to the natural soluble forms, and tested their ability to block MV infection. Vero cells and CHO cells expressing human MCP were the targets. Of the antibodies tested, M75 and M177, which blocked the C regulatory activity of MCP, efficiently blocked MV infection. More than 50 micrograms/ml of the soluble form moderately blocked MV infection of CHO cells expressing MCP, but barely blocked that of Vero cells. The two mAb and the soluble form also inhibited MV H protein-mediated green monkey erythrocyte rosette formation. A quantitative analysis suggested that 30 micrograms/ml of the soluble form functionally corresponded to 0.2 microgram/ml of M177 or M75. These data established that the C regulatory function and the MV receptor function of MCP were blocked simultaneously by the individual mAb, and that soluble forms of MCP could inhibit MV infection in cells expressing human MCP, although doses far higher than the natural concentration of soluble MCP were required.
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PMID:Blocking measles virus infection with a recombinant soluble form of, or monoclonal antibodies against, membrane cofactor protein of complement (CD46). 779 36

Human seminal plasma contains 0.55 microgram/ml of membrane cofactor protein (MCP; CD46) of 60,000 MW. By ultracentrifugation, gel filtration and immunoelectron microscope methods, we found that the MCP in seminal plasma was associated with prostasomes. The functional properties of the prostasome-bound MCP were assessed in comparison with a recombinant soluble form, gamma MCP1, which is composed of four short consensus repeats (SCR), type C of the serine/threonine-rich domain (STC), and unknown significance (UK). The MCP in seminal plasma, although demonstrably bound to prostasomes, behaved more like the soluble form of MCP. In the absence of detergent it, together with factor I, degraded the fluid-phase ligand, methylamine-treated C3 [C3(MA)], which is insensitive under no-detergent conditions to the membrane form of MCP and factor I. Moreover, C3dg fragment was generated as a final product instead of C3bi during the incubation, indicating that the prostasomal MCP and proteases may be responsible for the C3dg generation. The prostasomes neutralized measles virus (MV) infectivity, while gamma MCP1, for the most part, did not. These results, taken together with the CD59 concentration on the prostasomes, suggest that the prostasomes are potential immunomodulators for complement activation, providing the C3- and C9-step inhibitors. The present report also reinforces the idea that there are two different forms of MCP in semen. One is located in the inner acrosomal membrane of spermatozoa, which appears through acrosomal reaction and spermatoon-egg interaction. The other is a prostasome-bound form maintaining activities sufficient to regulate complement activation and, probably, MV infection.
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PMID:Membrane cofactor protein (CD46) in seminal plasma is a prostasome-bound form with complement regulatory activity and measles virus neutralizing activity. 779 37

Human membrane cofactor protein (MCP, CD46) is a receptor for the measles virus and serves as a complement regulator which protects host cells from autologous complement attack. MCP is highly polymorphic due to a variety of mRNA splice products. The levels of MCP expression on T and myeloid cell lines are usually two-eightfold higher than those on their normal counterparts, whereas Burkitt's lymphoma B cell lines express less MCP than B cell lineages carrying no EB virus. The molecule has a Ser/Thr-rich (ST) domain adjacent to the functional domain, namely short consensus repeats (SCR). The ST domain and a cytoplasmic tail (CYT) contribute to the MCP polymorphism. The ST domain is encoded by three exons (A, B and C) and major ST isoforms are STABC, STBC and STC. The authors investigated the relationship between the expression levels and isoform usage of MCP by flow cytometry using specific antibodies against STA and STC, by reverse transcriptase-polymerase chain reaction (RT-PCR) with size markers for each splice variant, and by RT-PCR/Southern blotting using a specific probe for STA. The results were (1) the profiles of mean shifts of myeloid and T cell lines were STC < STA on flow cytometry while those of B cell lines and normal blood cells were STA < STC; (2) all cell lines tested by RT-PCR expressed the messages for the isoforms STBC/CYT1, STC/CYT1, STBC/CYT2, and STC/CYT2. The band for STABC/CYT2 overlapped that for STC/CYT1, and the band for STABC/CYT1 was marginal in all cell lines examined; (3) semi-quantitative analysis of the STABC isoforms by Southern blotting indicated the presence of high levels of the STABC messages in myeloid and T-cell lines in comparison with B lymphoid cells and normal leucocytes. Thus, the quantity of MCP expressed parallels the STABC message level, which is up-regulated in T and myeloid leukaemia cell lines.
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PMID:High expression of membrane cofactor protein of complement (CD46) in human leukaemia cell lines: implication of an alternatively spliced form containing the STA domain in CD46 up-regulation. 855 81

Membrane cofactor protein (MCP, CD46) of the complement system is a measles virus (MV) receptor. Human lymphocytes express a heavily glycosylated (H) and a lightly glycosylated (L) form of MCP, which confers a two-band profile on SDS-PAGE the ratio of which is controlled genetically and organ-specifically. In contrast, granulocytes express a single heavily glycosylated form regardless of lymphocyte MCP phenotype. We investigated susceptibility to MV of granulocytes and lymphocytes from individuals with different lymphocyte MCP phenotypes. In any individual, granulocytes were > 10-fold less susceptible to MV than lymphocytes, and the lymphocytes with predominant H form were generally less susceptible to those with an increasing amount of L form. Thus, lymphocytes always exhibit high susceptibility to MV compared to granulocytes in all individuals. This finding may explain the lymphopenia and immunosuppression observed secondary to MV infection.
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PMID:Human lymphocytes are more susceptible to measles virus than granulocytes, which is attributable to the phenotypic differences of their membrane cofactor protein (CD46). 871 5

During measles virus (MV) infection, lymphopenia and immune suppression are observed in humans, yet the mechanisms underlying these effects remain unknown except that membrane cofactor protein (MCP, CD46) acts as a receptor for MV, accelerating entry of the virus into host cells. CD46 is a complement regulator, the role of which is to protect host cells from the autologous complement system. Thus, it encompasses complement-related and MV-mediated immune modulation. In this review, I discuss the structural and functional differences between CD46 on lymphocytes and on granulocytes, which partly explain the higher susceptibility of lymphocytes to MV than other blood cells to clarify the mechanisms of MV-mediated lymphopenia and immune suppression, and help resolve the T cell immunity dysfunction secondary to virus infection including HIV.
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PMID:CD46, a complement regulatory protein/measles virus receptor, and its relation to hematological disorders. 885 67

We isolated a 1257-bp cDNA encoding a membrane cofactor protein (MCP, CD46)/measles virus (MV) receptor-like protein from a cDNA library of Vero cells, in which wild MV strains were established. Vero cells contain MCP mRNA splice products encoding different cytoplasmic tails like human cells. The deduced amino acid sequence of the cDNA was 86% identical to that of human MCP. Vero cell MCP expressed on CHO cells was recognized by monoclonal antibodies against human MCP, and served as a potent MV receptor. In addition, Vero MCP was as effective as human MCP in human factor I-mediated C3b cleavage. Thus, the high MV susceptibility of Vero cells can in part be attributed to an MCP-like molecule that is structurally and functionally similar to human MCP.
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PMID:Molecular cloning of a complementary DNA for a membrane cofactor protein (MCP, CD46)/measles virus receptor on Vero cells and its functional characterization. 899 35

Two phosphatidylinositol (PI)-anchored versions of a measles virus (MV) receptor membrane cofactor protein (MCP; CD46) were generated by fusing the extracellular domain of MCP to the decay-accelerating factor (DAF; CD55) or its PI anchor. The PI-anchored forms of MCP expressed on Chinese hamster ovary cells, otherwise non-permissive to MV, conferred a smaller MV cytopathic effect than a wild-type MCP, a Ser/Thr-rich domain-deletion mutant and a cytoplasmic tail-deletion mutant of MCP. Therefore the differences in MV receptor properties between the two PI-anchored and three transmembrane forms were investigated. The PI-anchored forms were predominantly expressed on microvilli as in DAF, whereas the other transmembrane forms were found on intracellular membranes. The PI-anchored forms conferred high MV-binding capacity compared with the transmembrane versions. MV replication was, however, severely suppressed in cells expressing the PI-anchored forms, resulting in ineffective syncytium formation. In contrast, cell-to-cell fusion occurred efficiently after co-transfection of cDNA species encoding MV-H. MV-F and any version of MCP. Thus the PI-anchored forms, despite showing sufficient MV binding and cell-to-cell fusion competence together with MV-H and MV-F, mediate inefficient MV entry or replication, which causes severe suppression of the MV cytopathic effect. A biased receptor distribution on microvilli might participate in the selection of a low MV uptake pathway in the PI-anchored forms of MCP. Taken together, the transmembrane portion of MCP is a critical factor for effective virus-cell fusion and the subsequent MV replication.
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PMID:The CD46 transmembrane domain is required for efficient formation of measles-virus-mediated syncytium. 907 53

Measles virus (MV) infects not only human beings but also some simian species. The MV receptor on Vero cells (a cell line established from African Green monkey kidney cells) and human cells has been shown to be the membrane cofactor protein MCP/CD46, which is an inhibitor of autologous complement (C) activation. B95a, an Epstein-Barr virus (EBV)-transformed marmoset B cell line, is a simian cell line used for MV selection and is much more susceptible to MV than Vero cells. In the present study, we isolated cDNAs encoding MCP homologues from B95a cDNA library and assessed whether B95a-MCP is responsible for the high susceptibility of B95a to MV. The deduced amino acid sequence of the cDNA of B95a-MCP was 76% identical to that of human-MCP, and the recombinant B95a-MCP exerts C inhibitor activity. Although CAM, a vaccine strain of MV, infected Chinese hamster ovary (CHO) cells expressing B95a-MCP, Nagahata strain, a wild type of MV, failed to infect the CHO transfectants, suggesting that additional membrane molecules of B95a are responsible for the high susceptibility of B95a to the Nagahata strain.
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PMID:Molecular cloning of membrane cofactor protein (MCP; CD46) on B95a cell, an Epstein-Barr virus-transformed marmoset B cell line: B95a-MCP is susceptible to infection by the CAM, but not the Nagahata strain of the measles virus. 949 6

Membrane cofactor protein (MCP; CD46) is a type 1 membrane glycoprotein that inhibits complement activation on host cells. It also is a measles virus (MV) receptor, an adherence factor for group A Streptococcus pyogenes, and a cellular pilus receptor for pathogenic Neisseria. The amino terminus of MCP consists of four complement control protein (CCP) repeats, three of which (CCP-1, -2, and -4) possess N-glycans. Immediately following the CCP modules is an alternatively spliced region for extensive O-glycosylation (termed the STP domain). Previous studies established that the N-glycan of CCP-2 is essential for MV binding and infection and that the splicing variants of the STP domain not only affect MV binding and fusion, but also differentially protect against complement-mediated cytolysis. In this report, we dissect the role of these carbohydrates on complement regulatory function. We constructed, expressed, and characterized proteins deleting these carbohydrates. For MCP-mediated protection against cytolysis, the N-glycans of CCP-2 and -4 were necessary, the STP segment influenced but was not essential, and the N-glycan of CCP-1 was not required. In addition, the rate and magnitude of cell surface cleavage of C4b to C4c and C4d by MCP and factor I correlated with cytoprotection. These studies expand the structure-function understanding of the active sites of MCP and elucidate an important role for carbohydrates in its function, a finding consistent with their conservation in the MCP of other species.
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PMID:Membrane cofactor protein: importance of N- and O-glycosylation for complement regulatory function. 975 96


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