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:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebrospinal fluid contains several proteolytic enzymes that can degrade myelin basic protein (BP) under physiological conditions into peptide fragments of various sizes which still contain antigenic determinants capable of binding antibodies to BP. These enzymes are optimally active in either acid (pH 4) or nuetral (pH 7 to 8) conditions and can be characterized by the nature of the BP peptide fragments produced. Proteinases resembling cathepsin D, thrombin, plasmin (fibrinolysin), or kallikrein are present in variable amounts in CSF. No relationship to any particular disease has yet been established.
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PMID:Degradation of myelin basic protein by cerebrospinal fluid: preservation of antigenic determinants under physiological conditions. 9 75

Immunohistochemical studies were carried out on the new type of cerebral cortical astrocytic inclusions recently discovered in a 20-year-old patient with maldeveloped brain and micropolygyria. The inclusions appeared as eosinophilic structures (hematoxylin and eosin stain) and did not exhibit argyrophilia (modified Bielschowsky method). The inclusions were strongly stained by the antibody against S-100 protein (S 100) and to a lesser extent by the antibody to microtubule-associated protein 1B (MAP 1B). In contrast to Rosenthal fibers, the astrocytic inclusions did not react with antibodies to alpha B-crystallin, glial fibrillary acidic protein and ubiquitin. No positive reactions were obtained with antibodies against heat-shock protein 27 (HSP 27), HSP 72, actin, vimentin, desmin, cytokeratin, myelin basic protein, beta-tubulin, MAP 2, tau protein, paired helical filament, phosphorylated neurofilament protein (NFP), nonphosphorylated NFP, synaptophysin, cathepsin D, alpha 1-antichymotrypsin, alpha 1-antitrypsin and basic fibroblast growth factor. By immunoelectron microscopy, the products of the reaction with the anti-S 100 antibody appeared as heterogeneous granular deposits and with the antibody to MAP 1B they were randomly scattered throughout the astrocytic inclusions. Our results demonstrate that the immunohistochemical profile of the recently described inclusions differs from that of Rosenthal fibers. Whether the novel inclusions are involved in congenital astrocyte dysfunction and cerebral malformation remains to be established.
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PMID:Immunohistochemical studies on the new type of astrocytic inclusions identified in a patient with brain malformation. 133 66

Myelin basic protein (MBP) is a candidate Ag for the autoimmune process believed to be involved in the pathogenesis of multiple sclerosis (MS). To investigate the fine specificity and HLA restriction of human MBP-specific CTL, long term T cell lines (TCL) were established from 22 MS patients and 16 healthy individuals by repeated antigenic restimulation. By using this approach, MBP-specific cytotoxic TCL were generated from 81% of the lines from MS patients and 69% of those from controls. TCL from both groups expressed the CD3+, CD4+, CD8- phenotype and secreted substantial amounts of IFN-gamma. By using large enzymatic and small synthetic peptides of MBP, TCL were primarily specific for the C-terminal part of the molecule and to a lesser extent for the N-terminal portion. Two regions of the molecule, MBP peptide 87-106 and MBP peptide 154-172, were recognized by the majority of the polyspecific lines and by four and three of 14 monospecific TCL, respectively. These highly immunogenic regions are of interest because they include sequences encephalitogenic in other species. The HLA restriction of each line was determined by using antibody blocking as well as various target cells including EBV-transformed B cells, homozygous typing cells, and fibroblasts transfected with cDNA for DR-alpha and DR-beta genes. All TCL were restricted by HLA-DR Ag. Several HLA-DR molecules restricted multiple cathepsin D-derived and synthetic MBP peptides, including the regions of peptides 87-106 and 154-172 which, respectively, were recognized in conjunction with four and three HLA-DR types. Three of these HLA-DR types are overrepresented in MS patients in different geographic regions. Together, these findings suggest that the MBP-specific cytotoxic T cell response, although not sufficient for disease, may be important for the pathogenesis of MS.
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PMID:Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. 169 81

Rabbit myelin basic protein (BP) was subjected to partial cleavage with plasmin, and 15 cleavage products were isolated by a combination of gel filtration and ion-exchange chromatography. Their identification was achieved by amino acid analysis and tryptic peptide mapping, supplemented in some instances by carboxy-terminal analyses with carboxypeptidases A, B, and Y and amino-terminal analyses with dipeptidyl aminopeptidase I. The results showed that major plasmic cleavage sites included the Lys89-Asn90, Lys133-Ser134, and Lys153-Leu154 bonds. Cleavages also occurred at the Arg31-His32, Lys53-Arg54, and Arg25-His26 bonds, but these appeared to be less extensive. A large number of additional peptides were produced in relatively low yield. The smaller of these were isolated from heterogeneous fractions by high-voltage electrophoresis-TLC. Amino acid analysis of these peptides showed that minor cleavage sites included the Arg9-His10, Lys13-Tyr14, Lys103-Gly104, Lys137-Gly138, Lys140-Gly141, and Arg160-Ser161 bonds. In spite of a lower selectivity toward peptide bonds in BP as compared with pepsin, cathepsin D, and thrombin, plasmin has the advantage over the former proteinases in that it does not cleave at or near the Phe44-Phe45 bond. Instead it cleaves at the Arg31-His32 and Lys53-Arg54 bonds, thus preserving the entire hydrophobic sequence Ile-Leu-Asp-Ser-Ile-Gly-Arg-Phe-Phe as well as short sequences to either side.
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PMID:Cleavage of rabbit myelin basic protein by plasmin: isolation and identification of the major products. 241 69

Some acidic lipids including sulfatide and phosphatidylinositol were found to increase greatly the rate of cathepsin D cleavage of the myelin basic protein. Since a similar effect was seen when the substrate was changed to cytochrome C, but not when the enzyme was changed to pepsin, these acidic lipids seem to be acting on cathepsin D rather than on myelin basic protein itself. Even so, chemical modification studies suggest that this phenomenon is only seen when the myelin basic protein is in its native conformation. Succinylation of MBP increases its rate of cleavage by cathepsin D by at least tenfold and, in addition, with this modified and presumably denatured MBP as substrate, activation of cathepsin D is no longer seen with acidic lipids. These findings suggest that the native conformation of MBP is both an important determinant of its rate of cleavage by cathepsin D and is also essential for observing activation of this reaction by acidic lipids. The acidic lipids seem to alter the "extended active site" of cathepsin D in such a way as to enable this enzyme better to utilize the native myelin basic protein as a substrate. Cathepsin D has previously been implicated as the protease responsible for the release into cerebrospinal fluid in multiple sclerosis patients of an encephalitogenic fragment derived from myelin basic protein. It is possible that the elevated levels of cathepsin D and sulfatide that have previously been found associated with multiple sclerosis plaques in vivo act in concert to bring about the rapid cleavage and subsequent loss of the myelin basic protein from these localized regions in the myelin sheath.
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PMID:Acidic lipids enhance cathepsin D cleavage of the myelin basic protein. 242 Oct 4

Experimental spinal cord injury was produced in rats by dropping a 10 g weight from 30 cm upon dura-invested exposed spinal cord. Proteolytic activities at neutral (pH 7.6) and acid (pH 5.5 and 3.6) pH were determined in whole homogenate and the cytosolic fraction of the lesion (lumbar) and cervical control segments. The enzyme activity was monitored by SDS-PAGE analysis of the extent of substrate myelin basic protein (MBP) degradation. Activities (neutral and cathepsin B-like) in the sham-operated spinal cord were lower than those of cervical autologous control at 24 h after injury. The increase in neutral proteinase activity was progressive and greater in the lesion than the autologous control. A 61.5% +/- 3.5 loss of MBP was observed at 2 h following injury and increased at 24 h (78.2% +/- 3.4). The loss of MBP coincided with the appearance of several low molecular weight peptides. The cathepsin B-like and cathepsin D activities were also increased in the lesion but to a lesser extent than the neutral proteinase. The neutral proteinase and cathepsin B-like activity were inhibited by leupeptin and not by pepstatin while the converse obtained for cathepsin D activity. The release of neutral proteolytic activity which is nonlysosomal in origin suggests a novel hypothesis for the mechanism of traumatic axon-myelin injury.
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PMID:Proteolytic enzymes in experimental spinal cord injury. 242 54

A new two-dimensional polyacrylamide gel electrophoresis (PAGE) system with minislab gel apparatus was devised for the rapid (4 h) analysis of peptide fragments derived from the enzymic digestion of myelin basic protein (MBP). The first dimension consisted of 5% polyacrylamide running gels in 1.9 M potassium glycinate, pH 7.3, with 4.3% stacking gels in 0.08 M potassium glycinate, pH 10.3. Anodic and cathodic buffer chambers contained 38 mM glycine/5 mM Tris, pH 8.3, and 10 mM Tris-HCl, pH 8.1, respectively. This system fractionated MBP peptides on the basis of charge. By contrast, acid-urea 15% PAGE separated MBP peptides by both charge and size. A two-dimensional system of 5% PAGE followed by sodium dodecylsulfate 15% PAGE (Laemmli) was used to resolve MBP fragments from pepsin and cathepsin D digests; this analysis indicated that cathodic mobilities could be predicted by the ratio of basic to acidic amino acids in each peptide. This method should be particularly powerful in combination with immunoblotting to identify microheterogenous fragments arising from normal and pathological metabolism of MBP.
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PMID:Two-dimensional electrophoretic characterization of microheterogeneous myelin basic protein fragments. 243 62

Both bovine and human myelin basic protein (MBP) have been shown to have electrophysiological activity. As MBP is susceptible to proteolytic degradation, our aim was to discover whether the resulting peptides retained this activity. Bovine MBP was completely cleaved by plasmin into at least nine peptides. The electrophysiological activities of this peptide mixture and of bovine MBP were directly compared on the hemisected frog spinal cord. The peptide mixture and intact bovine MBP had quantitatively and qualitatively similar effects (dose-dependent long-lasting depolarization, about 100 times more active than glutamate). Four peptides (molecular weights 14,000, 10,500, 8,000, 4,500) from thrombin or cathepsin D cleavage of bovine MBP also showed electrophysiological activity, positively correlated to their molecular weights. As MBP-like material occurs in increased concentrations in the cerebrospinal fluid during demyelinating diseases, peptides resulting from proteolytic degradation of MBP, e.g. in demyelinating foci of multiple sclerosis, might cause neuronal disturbances.
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PMID:Effects of peptides from bovine myelin basic protein on the bioelectrical activity of the frog spinal cord. 245 64

Isolated myelin of bovine spinal cord was found to degrade exogenous myelin basic protein (MBP) at pH 4.4. Electrophoretic peptide patterns were consistent with limited proteolysis of MBP. Some of the proteolytic activity was soluble at increased ionic strength, some remained bound, withstanding extraction at 37 degrees C for up to 12 hr. While being measurable with exogenous MBP, bound protease degraded neither bound MBP nor any other major intrinsic myelin protein. Both soluble and bound protease activity was completely inhibited by pepstatin A. The patterns of limited proteolysis of MBP they produced were identical. Myelin of cerebral white matter also exhibited soluble and bound acid protease activity which was likewise inhibited by pepstatin A. Protease activity of spinal cord and cerebral myelin is therefore suggested to be due to a cathepsin D-like endopeptidase, present in a loosely and tightly bound form. Both forms increased by 50 to 80% in activity when myelin was isolated from mixtures of white and cortical gray matter. While increased soluble activity of myelin is consistent with binding of cathepsin D of lysosomal origin during the isolation of myelin the tightly bound form might point to a principal mechanism through which exogenous proteins may become attached to the myelin sheath in vivo.
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PMID:Soluble and bound acid protease activity of myelin from bovine cerebral white matter and spinal cord. 245 76

Human myelin basic protein was fractionated into its various charge isomers by CM52 cation exchange chromatography. Approximately 25-30% of the total charge applied to the column appeared in the void volume. This material termed "C-8," was further purified by reversed phase high performance liquid chromatography. Amino acid analyses of C-8 revealed low Arg (7 residue % in C-8 compared to 11-12 residue % in C-1) and increased Glx residues. The low Arg was accounted for by a corresponding amount of citrulline. Sequence analysis after chemical fragmentation (cyanogen bromide and BNPS-skatole) and enzymatic (cathepsin D and carboxypeptidase S-1) digestion localized the citrulline at residues 25, 31, 122, 130, 159, and 170 of the amino acid sequence. The effect of this loss of positive charge on the ability of the protein to aggregate lipid vesicles was demonstrated with vesicles composed of phosphatidylcholine (92.2 mol %) and phosphatidylserine (7.8 mol %). C-1 was the most effective charge isomer, and C-8 was the least effective. The ability of these charge isomers to aggregate vesicles correlated with the net positive charge on each. Vesicles composed of phosphatidylcholine alone were not aggregated by lipophilin or any of the charge isomers. However, when lipophilin was incorporated into phosphatidylcholine vesicles (50% w/w), small, optically clear suspensions of vesicles were formed. None of C-1, C-2, or C-3 aggregated these vesicles, but C-8 produced rapid vesicle aggregation. Since the substitution of citrulline for Arg would generate several relatively long apolar sequences, these would enhance the ability of C-8 to interact with the hydrophobic lipophilin molecule, promoting vesicle aggregation by hydrophobic interactions. The mechanism by which citrulline is generated in myelin is not known, although enzymatic conversion has been described in other systems. Studies are underway to elucidate the mechanism by which this post-translational modification is generated.
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PMID:The isolation, characterization, and lipid-aggregating properties of a citrulline containing myelin basic protein. 246 44


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