Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cysteine protease inhibitor was purified from total membrane fractions of an invasive murine hepatoma, Hepa cl 9. On gel filtration under non-reducing conditions the purified inhibitor was eluted in a single peak of M(r) 10-15 kDa, but resolved as two bands at 14 and 70 kDa on SDS-PAGE under reducing conditions. By isoelectric focusing, the inhibitor ran at an isoelectric point of 4.75. Immunoblotting studies using the enhanced chemiluminescence technique indicated no crossreactivity with monoclonal antibodies to stefin B and cystatin C or with a polyclonal antibody to low M(r) kininogen. In contrast, the 14 kDa and 70 kDa bands both crossreacted with a polyclonal antibody to stefin A, suggesting that the cysteine protease inhibitor associated with Hepa cl 9 membranes may be a modified form of stefin A.
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PMID:A membrane-associated cysteine protease inhibitor from murine hepatoma. 151 98

Cystatin C, a cysteine protease inhibitor, has recently been suggested to be a potent regulator in inflammatory processes. Human cystatin C was isolated from the urine of one patient suffering from tubular disorders and was tested for its effects on two functions of human polymorphonuclear neutrophils (PMN): O2- release and phagocytosis. Slow-form or (des 1-4) cystatin C and fast-form or (des 1-8) cystatin C differed by the presence in (des 1-4) cystatin C only of the N-terminal tetrapeptide Lys-Pro-Pro-Arg. Whereas (des 1-8) cystatin C did not seem to interfere with PMN functions at physiological concentrations, (des 1-4) cystatin C induced an inhibition of PMN phagocytosis-associated respiratory burst in response to opsonized zymosan particles. The inhibition may be attributed to the tetrapeptide Lys-Pro-Pro-Arg which has been synthesized and shown to have the same inhibitor effects, at concentrations similar to those required for (des 1-4) cystatin C. These results support a potential role for cystatin C as a modulator during inflammation.
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PMID:Modulation of phagocytosis-associated respiratory burst by human cystatin C: role of the N-terminal tetrapeptide Lys-Pro-Pro-Arg. 215 59

Differential screening of a cDNA library derived from mRNA of TGF beta-treated serum-free mouse embryo (astrocyte precursor) cells isolated a strongly TGF beta-regulated mRNA that codes for cystatin C, a cysteine protease inhibitor. Increase in cystatin C mRNA level was observed within four hours after treatment with picomolar concentrations of TGF beta. The increase was reversible upon removal of TGF beta and was not prevented by cycloheximide. These results suggest that cystatin C expression may represent a developmentally regulated differentiated function of astrocytes, and also suggest that cystatin C expression may be involved in the response of brain cells to platelet release of TGF beta after trauma or injury.
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PMID:Transforming growth factor beta regulates cystatin C in serum-free mouse embryo (SFME) cells. 224 83

A gamma-trace variant protein is the major constituent of the amyloid fibrils in patients from Iceland with hereditary cerebral hemorrhage with amyloidosis. The protein consists of 110 residues and is similar to human urinary gamma-trace basic protein (or cystatin C) beginning at its 11th amino-terminal residue. It has an amino acid substitution (glutamine for leucine) at position 58 (position 68 in gamma-trace numbering), which is near the proposed active site of related proteins--namely, cysteine protease inhibitors and kininogens. It is postulated that a point mutation has occurred, leading to the production of an unusual protein that is abnormally degraded, bound, and/or precipitated. Alternatively, gamma-trace basic protein may be genetically polymorphic, and the variant described here may represent an as-yet-undiscovered isotype or an allelic form that is linked to, but not responsible for, the deposition disease. Our data on the structure of a gamma-trace variant protein suggests that its gene expresses a polyprotein precursor in which active peptides are flanked by basic amino acid residues that permit cleavage to liberate small internal peptides. It is likely that the nucleotide sequence coding for Arg-Xaa and Lys-Xaa repeated several times in the molecule may function as alternative splicing sites for mRNA processing.
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PMID:Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). 351 80

Cysteine proteases of the papain family generally exhibit broad P1 specificity. A notable exception is papaya proteinase IV (PPIV), which only accepts Gly at this position. In all other cysteine proteases the S1 subsite residues 23 and 65 (papain numbering) are absolutely conserved as Gly, while in PPIV they are replaced by Glu and Arg, respectively. These differences appear to underlie both PPIV specificity and its resistance to inhibition by cystatins. To test this hypothesis, the equivalent residues (Gly27 and Gly73) in the mammalian cysteine protease cathepsin B were changed to Glu and Arg, respectively. Relative to the wild-type enzyme, the Gly27Glu and Gly73Arg mutants showed a drastic reduction in activity with substrates containing a P1 Arg. In contrast, substrates having a Gly residue in P1 were hydrolyzed effectively. The double mutant (Gly27Glu:Gly73Arg) exhibited no detectable activity against any substrate studied. Inhibition of the Gly73Arg mutant by E-64 [1-(L-trans-epoxysuccinyl-L-leucylamino)-4-guanidinobutane] was found to be similar to that of the wild-type enzyme. In contrast, inhibition by cystatin C exhibited a 20,000-fold reduction. These results demonstrate the dramatic influence of side chains at sequence locations 27 and 73 on the S1 subsite specificity of cysteine proteases.
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PMID:Modification of S1 subsite specificity in the cysteine protease cathepsin B. 777 Apr 53

Cystatin C, a cysteine protease inhibitor, was subject to hydrolysis at two sites when complexed with papain and in the presence of excess papain. A pH-dependent cleavage at His-86 increases Asp-87 was observed, as well as a pH-independent one at Gly-4 increases Lys-5. His-86 increases Asp-87 hydrolysis increased with decreasing pH and was characterized kinetically. It could be described by a single ionization with pKa = 3.4 +/- 0.2 and (kcat./Km)max. = 1.4 (+/- 0.4) x 10(4) M-1.s-1 at I = 0.3 M. C.d. spectroscopy, also at I = 0.3 M, demonstrated a conformational change with pKa = 3.2 +/- 0.2, indicating that the pH-dependence of hydrolysis was due to a conformational change in cystatin C. At I = 0.15 M, the pKa of the conformational change observed by c.d. shifted to 4.1 +/- 0.1. This indicates that at physiological ionic strength of 0.15 M, a significant proportion of cystatin C complexed with protease would be in a proteolytically labile conformation over the pH range 4.5 to 5, which is encountered in lysosomes. This may constitute a mechanism for clearing inappropriately localized cystatins. A pH-dependent conformational variability in this region of the inhibitor could explain the differences in the X-ray crystallographic and n.m.r. structures of the homologous chicken cystatin. The ionic-strength dependence of ionization indicates a hydrophobic stabilization of the ionizable group. The lack of pH-dependence of hydrolysis at Gly-4 increases Lys-5, with kcat./Km = 220 +/- 41 M-1.s-1 in the pH range 3.89 to 7.96 was unexpected in light of the normal, bell-shaped pH-dependence of papain-catalysed hydrolyses. This may reflect a different rate-limiting step of cystatin C hydrolysis.
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PMID:Local pH-dependent conformational changes leading to proteolytic susceptibility of cystatin C. 809 91

'Prohormone thiol protease' (PTP) represents the major enkephalin precursor processing activity in chromaffin granules. In this study, cleavage specificity of PTP for paired basic and monobasic residues was examined with a series of model peptide-MCA (-methylcoumarinamide) substrates. Monobasic peptides were cleaved at the COOH- and NH2-terminal sides of the single basic residue. Dibasic peptides, however, were preferentially cleaved at the NH2-terminal side of the pair, or between the two basic residues, with low cleavage at the COOH-terminal side of the pair. Inhibition by the peptide inhibitor (D-Tyr)-Glu-Phe-Lys-Arg-CH2Cl provided further evidence for PTP's specificity for the dibasic Lys-Arg site. Inhibition by Z-Leu-Val-Gly-CHN2 and Z-Arg-Leu-Val-Gly-CHN2 suggests involvement of Val-Gly in substrate binding to PTP; these two cystatin C-related inhibitors also indicate PTP as a cysteine protease. These results demonstrate PTP's unique cleavage specificity that differs from other processing endopeptidases, including the subtilisin-related proprotein convertases, PC1/PC3, and PC2, as well as the pituitary proopiomelanocortin-converting enzyme, PCE. This study provides further evidence for PTP as a novel prohormone processing enzyme that belongs to the class of cysteine proteases.
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PMID:Unique cleavage specificity of 'prohormone thiol protease' related to proenkephalin processing. 813 39

Sertoli cells were shown to synthesize and secrete cystatin C, a potent inhibitor of cysteine proteases. The evidence for this observation was obtained from protein sequencing. Western analysis using antiserum specific to cystatin C, and immunoprecipitation of 35S protein secreted by cultured cells. The Western analysis with an antiserum to human cystatin C showed that cultured Sertoli cells secrete three previously reported immunoreactive forms of cystatin C: a predominant pair of proteins at 13-14 kDa and a less abundant 20-kDa protein. Immunohistochemical localization of cystatin C in sections of rat testes showed intense staining in Sertoli cells; no immunoreactivity was observed in spermatogonia or spermatocytes. A cDNA fragment for rat cystatin C was obtained by use of the polymerase chain reaction and was used as a probe in Northern analyses to examine the steady-state levels of cystatin C mRNA in intact testes and in Sertoli and spermatogenic cells. Sertoli cells contained a 700-nucleotide cystatin C transcript, and a mixed population of spermatids and spermatocytes contained a 550-nucleotide transcript. Analysis of RNA from purified spermatogenic cells revealed that round and condensing spermatids contained the 550-nucleotide transcript, while pachytene spermatocytes contained a smaller 500-nucleotide transcript. The 700-nucleotide transcript was present in testes isolated from rats of 5-79 days of age, the 500-nucleotide transcript was detected initially in testes from 24-day-old rats, and the 550-nucleotide transcript was detected initially at 35 days of age. Both the 500- and 550-nucleotide transcripts increased in abundance until 50 days of age. RNA from stage-synchronized testes showed that steady-state levels of both the 550- and 700-nucleotide transcripts were lowest in stages VI-VII of the cycle. These data suggest that the role of cystatin C in the testis may be to inhibit the proteolytic activity of the cysteine protease cathepsin L in all stages except stages VI-VII.
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PMID:Sertoli cell and germ cell cystatin C: stage-dependent expression of two distinct messenger ribonucleic acid transcripts in rat testes. 828 70

The effect of different protease inhibitors on the proteolytic processing of the plum pox potyvirus (PPV) polyprotein has been analyzed. Human cystatin C, an inhibitor of cysteine proteases, interfered with the autoprocessing of the viral papain-like cysteine protease HCPro. Unexpectedly, it also had an inhibitory effect on the autocatalytic cleavage of the Nla protease which, although it has a Cys residue in its active center, has been described as structurally related to serine proteases. Other protease inhibitors tested had no effect on any of the cleavage events analyzed.
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PMID:Inhibitory effects of human cystatin C on plum pox potyvirus proteases. 834 5

Cystatin C, a cysteine protease inhibitor produced by the choroid plexus and found in CSF at high concentrations, may have an important role in brain injury. We used the two-vessel occlusion model with hypotension to induce transient forebrain ischemia (TFI) in rats for 10 min and then examined cystatin C immuno-like reactivity (CC-IR) after 1, 3, 7 and 14 days of recovery. Our results reveal that CC-IR was minimal or absent in the hippocampus of normal and 1 day post-ischemic animals. However, CC-IR was present in CA1 pyramidal cells and a small number of reactive glia of the stratum radiatum (SR) and stratum oriens (SO) at 3, 7 and 14 days post-ischemia. Histological assessment of the hippocampus indicates that CC-IR was localized in morphologically degenerative neurons. This distinct temporal expression of cystatin C in the rat hippocampus is concurrent with delayed neuronal death following TFI. Thus, these results indicate that cystatin C and/or its substrates may be important components of the post-ischemic neurodegenerative and repair process.
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PMID:Cystatin C, a protease inhibitor, in degenerating rat hippocampal neurons following transient forebrain ischemia. 859 41


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