Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using an indirect immunoperoxidase technique, we tested frozen specimens from 12 Wilms' tumors with monoclonal antibodies (MoAbs) reacting against a large panel of molecules including laminin, fibronectin, cytokeratin, vimentin, villin, CD24, CALLA/CD10, CR1, CD26, class I and class II major histocompatibility complex (MHC) molecules, and endothelium factor VIII. These molecules were chosen because they are markers of specific segments of the mature kidney and because their loss or acquisition is indicative of different steps of human nephrogenesis. KI67 MoAb was used to evaluate the proliferating activity of the cells. The blastemal component (cell compact areas) of Wilms' tumors consisted of vimentin-positive cells with a fibronectin network. However, signs of epithelial maturation were present in compact areas where cytokeratin-positive cells producing laminin were observed. The cells exhibited a high degree of proliferating activity. The tubule formations consisted of cytokeratin-positive cells and had a defined laminin border. All the cells, whether in compact areas or in tubules, were strongly CD24-positive. Some tubular formations showed signs of proximal maturation with the presence of CALLA, CD26, and even villin. In four cases class I-MHC molecules were expressed by some tubular cells. Large cystic cavities present in five cases were edged by cytokeratin, CD24-positive cells, or by vimentin, CALLA, CR1-positive cells. Some glomeruloid bodies, present in two cases, were also composed of vimentin, CALLA, and CR1-positive cells which correspond to the mature podocyte phenotype. The interstitial tissue contained mainly laminin and fibronectin network with macrophages and few CD3 lymphocytes. The presence of large cells with muscular differentiation was noted; round vimentin and CD26-positive cells were also seen. The endothelial cells of the vessels exhibited vimentin, factor VIII, and class I and class II MHC molecules as do mature cells, but in some cases the endothelial cells lacked class II molecule expression and were CALLA-positive. These results which confirmed and extended those previously described show that cell differentiation in Wilms' tumor mimics that observed during metanephros development. Moreover, this study shows that tumoral cells in nephroblastoma share several antigens with cells from lymphoid lineage (CD24, CALLA, and CD26) as do developing and mature kidney cells. Such cell phenotype dissection provides a useful and reliable tool for testing the influence of various factors on the development of hetero-transplanted or cultured Wilms' tumors.
 ...
PMID:Cell differentiation in Wilms' tumor (nephroblastoma): an immunohistochemical study. 169 63

Meprin, a glycoprotein with potent metalloendopeptidase activity, is an integral component of the brush border membrane of mouse kidney. Previously we reported that genealogically related inbred mouse strains (C3H and CBA) are markedly deficient in the activity of this enzyme. We report here that meprin deficiency is inherited as an autosomal recessive trait and that several other inbred strains also express low levels of meprin activity. All of the inbred strains deficient in meprin activity are of the H-2k haplotype; however, two strains of this haplotype (C58 and C57BR/cd) expressed normal levels of the proteinase. Congeneic and recombinant mouse strains were examined to determine whether the deficiency was linked to the H-2 complex. The gene controlling the activity of meprin (Mep-1) maps on chromosome 17 to the right of the D end of the major histocompatibility complex. The Mep-1 gene is closely linked to a gene that controls isoenzyme patterns of phosphoglycerate kinase (Pgk-2). This work represents the localization of a gene that determines the activity of an integral cellular endopeptidase in mammalian tissues. In addition, the Mep-1 gene is the only identified gene linked to the major histocompatibility complex that regulates a proteinase activity.
 ...
PMID:Mep-1 gene controlling a kidney metalloendopeptidase is linked to the major histocompatibility complex in mice. 638 65

The determination of peptide stability in human serum (HS) or plasma constitutes a powerful screening assay for eliminating unstable peptides from further development. Herein we report on the stability in HS of several major histocompatibility complex (MHC)-binding peptides. Some of these peptides are in development for the novel treatment of selected autoimmune disorders such as rheumatoid arthritis and insulin-dependent diabetes. For most of the l-amino acid peptides studied, the predominant degradation mechanism is exopeptidase-catalyzed cleavage. Peptides that were protected by d-amino acids at both termini were found to be more stable than predicted, based on additivity of single substitutions. In addition, N-acetylglucosamine glycopeptides were significantly stabilized, even when the glycosylation site was several amino acids from the predominant site(s) of cleavage. This indicates that long-range stabilization is possible, and likely due to altered peptide conformation. Finally, the effect of single amino acid substitutions on peptide stability in HS was determined using a model set of poly-Ala peptides which were protected from exopeptidase cleavage, allowing the study of endopeptidase cleavage pathways.
 ...
PMID:Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. 823 61

Proteasomes are highly conserved macromolecular structures which function as endopeptidases. They are found in the cytoplasm and nucleus of eukaryotic tissues and consist of at least 14 non-identical subunits with molecular masses ranging from approximately 20 to 32K. Proteasomes are essential in the selective degradation of ubiquitinated and certain non-ubiquitinated proteins, acting as the proteolytic core of an energy-dependent 26S (1,500K) proteolytic complex. Two proteasome subunits, LMP2 and LMP7 (refs 4-7), are encoded within the major histocompatibility complex (MHC), implicating proteasomes in antigen processing. Here we determine the function of these two MHC-linked subunits by comparing the proteolytic activities of purified proteasomes containing (LMP+) or lacking (LMP-) these components. We find that proteasomes of both types have endopeptidase activity against substrates bearing hydrophobic, basic or acidic residues immediately preceding the cleavage site (the P1 position) and at sites following asparagine, glycine and proline residues. The activity of LMP+ proteasomes is much higher than that of LMP- proteasomes against substrates with hydrophobic, basic or asparagine residues at P1, whereas their activities are comparable when acidic and glycine residues are present at P1. The MHC-linked LMP2 and LMP7 subunits therefore function to amplify specific endopeptidase activities of the proteasome.
 ...
PMID:MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. 837 76

The crystal structure of the 20S proteasome from the yeast Saccharomyces cerevisiae shows that its 28 protein subunits are arranged as an (alpha1...alpha7, beta1...beta7)2 complex in four stacked rings and occupy unique locations. The interior of the particle, which harbours the active sites, is only accessible by some very narrow side entrances. The beta-type subunits are synthesized as proproteins before being proteolytically processed for assembly into the particle. The proforms of three of the seven different beta-type subunits, beta1/PRE3, beta2/PUP1 and beta5/PRE2, are cleaved between the threonine at position 1 and the last glycine of the pro-sequence, with release of the active-site residue Thr 1. These three beta-type subunits have inhibitor-binding sites, indicating that PRE2 has a chymotrypsin-like and a trypsin-like activity and that PRE3 has peptidylglutamyl peptide hydrolytic specificity. Other beta-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.
 ...
PMID:Structure of 20S proteasome from yeast at 2.4 A resolution. 908 96

The CD19-CD21-CD81 complex regulates signal transduction events critical for B lymphocyte development and humoral immunity. CD81, a molecule with 4 transmembrane domains, member of the tetraspan superfamily, is engaged, together with other tetraspans such as CD9, CD53, CD63, and CD82, in multimolecular complexes containing beta1 integrins and major histocompatibility complex antigens. Here we demonstrate that two other tetraspans, CD82 and the early B cell marker CD9, are coimmunoprecipitated with CD19 from Brij97 lysates of B cell lines. Moreover, CD9 was coprecipitated from lysates of purified CD10(+) early B cells. These associations were confirmed by the cocapping of CD19 with CD9 or CD82. The CD9/CD19 association was disrupted in the presence of digitonin, contrary to the CD81/CD19 association, indicating that CD9 and CD81 interact with CD19 in different ways. The CD9/CD81 association is also disrupted in the presence of digitonin, suggesting that CD9 associates with CD19 only through CD81. To characterize the regions involved in the CD81/CD19 association, two reciprocal CD9/CD81 chimeric molecules were tested for the association with CD19, but none of them could be coprecipitated with CD19 in digitonin, indicating that the domain of CD81 responsible for its association with CD19 is complex. Finally, engagement of CD9 could induce the tyrosine phosphorylation of different proteins, including CD19 itself, suggesting that the CD9/CD19 association is functionally relevant. Thus, a physical and functional link is formed between the CD19-CD21-CD81 complex and the integrin-tetraspan complexes, which is dynamically modulated in the process of B cell differentiation.
 ...
PMID:CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. 980 23

Nearly all peptides generated by proteasomes during protein degradation are digested rapidly to amino acids, but a few proteasomal products escape this fate and are presented to the immune system on cell surface major histocompatibility complex class I molecules. To test whether these antigenic peptides may be inherently resistant to cytosolic peptidases, six different antigenic peptides were incubated with HeLa cell extracts. All six were degraded rapidly by a process involving o-phenanthroline-sensitive metallopeptidases. One antigenic peptide, FAPGNYPAL, was rapidly destroyed in the extracts by a bestatin-sensitive exopeptidase, apparently by the puromycin-sensitive aminopeptidase. The disappearance of the other five was reduced 30-90% by a specific inhibitor of the cytosolic endopeptidase, thimet oligopeptidase (TOP) (EC ), whose physiological function(s) have been unclear and controversial. All these peptides were sensitive to pure recombinant TOP. Furthermore, upon fractionation of the extracts, the major peptidase peak that degraded the ovalbumin-derived epitope, SIINFEKL, co-purified with TOP. In the extracts, TOP also catalyzed rapid degradation of N-extended variants of SIINFEKL and of other antigenic peptides, which in vivo can serve as precursors of these major histocompatibility complex-presented epitopes. This enzyme (unlike cell proteins that promote production of antigenic peptides) is not regulated by interferon-gamma. TOP seems to be primarily responsible for the rapid breakdown of antigenic peptides in cytosolic extracts, and our related studies (A. X. Y. Mo, K. Lemerise, W. Zeng, Y. Shen, C. R. Abraham, A. L. Goldberg, and K. L. Rock, submitted for publication) indicate that TOP by destroying such peptides limits antigen presentation in vivo.
 ...
PMID:Major histocompatibility complex class I-presented antigenic peptides are degraded in cytosolic extracts primarily by thimet oligopeptidase. 1147 11

The rules governing which T cells are inactivated during peptide-induced tolerance are unclear. Here we show that MBP(89-101) contains three overlapping but distinct T cell epitopes that are restricted by a single major histocompatibility complex (MHC) class II molecule. The dominant epitope is not processed from MBP and is not relevant to the induction of autoimmunity. Pathogenic T cells recognize two minor epitopes that are processed from MBP but are presented only poorly after exposure to MBP(89-101). Induction of immunological tolerance by MBP(89-101) therefore inactivates T cells that recognize the dominant epitope and disease-relevant T cells escape tolerance. The topology of the three epitopes implicates asparagine endopeptidase as the enzyme that controls recognition of this region of MBP. Our results highlight the need to use peptides that mimic the binding of processed antigen fragments to MHC molecules for successful modulation of disease-relevant T cells.
 ...
PMID:Influence of a dominant cryptic epitope on autoimmune T cell tolerance. 1181 83

Neuropeptide processing metalloenzymes, such as angiotensin converting enzyme, neprilysin, endothelin converting enzyme, neurolysin, and EC3.4.24.15 (EP24.15), are central to the formation and degradation of bioactive peptides. We present EP24.15 as a paradigm for novel functions ascribed to these enzymes in the neurome. Although the neurome typically encompasses proteomes of the brain and central nervous system, exciting new roles of these neuropeptidases have been demonstrated in other organ systems. We discuss the involvement of EP24.15 with clinical sequelae involving the use of gonadotropin-releasing hormone (GnRH; LHRH) analogs that act as enzyme inhibitors, in vascular physiology (blood pressure regulation), and in the hematologic system (immune surveillance). Hemodynamic forces, such as cyclic strain and shear stress, on vascular cells, induce an increase in EP24.15 transcription, suggesting that neuropeptidase-mediated hydrolysis of pressor/depressor peptides is likely regulated by changes in hemodynamic force and blood pressure. Lastly, EP24.15 regulates surface expression of major histocompatibility complex Class I proteins in vivo, suggesting that EP24.15 may play an important role in maintenance of immune privilege in sites of increased endogenous expression. In these extraneural systems, regulation of both neuropeptide and other peptide substrates by neuropeptidases indicates that the influence of these enzymes may be more global than was anticipated previously, and suggests that their attributed role as neuropeptidases underestimates their physiologic actions in the neural system.
 ...
PMID:Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome. 1459 22

Post-translational protein modifications can be recognized by B and T lymphocytes and can potentially make "self"-proteins appear foreign to the immune system. Such modifications may directly affect major histocompatibility complex-restricted T cell recognition of processed peptides or may perturb the processing events that generate such peptides. Using the tetanus toxin C fragment protein as a test case, we show that spontaneous deamidation of asparagine residues interferes with processing by the enzyme asparagine endopeptidase (AEP) and contributes to diminished antigen presentation. Deamidation inhibits AEP action either directly, when asparagine residues targeted by AEP are modified, or indirectly, when adjacent Asn residues are deamidated. Thus, deamidation of long-lived self-proteins may qualitatively or quantitatively affect the spectrum of self-peptides displayed to T cells and may thereby contribute to the onset or exacerbation of autoimmune disease.
 ...
PMID:Asparagine deamidation perturbs antigen presentation on class II major histocompatibility complex molecules. 1574 6


1 2 Next >>