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PubMed2005

3D domain-swapped human cystatin C with amyloidlike intermolecular beta-sheets.

Oligomerization of human cystatin C (HCC) leads to amyloid deposits in brain arteries, and this process is greatly accelerated with a naturally occurring L68Q variant. The crystal structures of N-truncated and full-length HCC (cubic form) showed dimer formation via three-dimensional (3D) domain swapping, and this observation has led to the suggestion that an analogous domain-swapping mechanism, but propagated in an open-ended fashion, could be the basis of HCC fibril formation. Here we report that full-length HCC, when crystallized in a new, tetragonal form, dimerizes by swapping the same secondary structure elements but with a very different overall structure generated by the flexibility of the hinge linking the moveable elements. The beta-strands of the beta-cores of the two folding units of the present dimer are roughly parallel, while they formed an angle of about 100 degrees in the previous two structures. The dimers pack around a crystallographic dyad by extending their molecular beta-sheets in an intermolecular context. At the other edge of the molecular beta-sheet, side-chain-side-chain hydrogen bonds propagate the beta-structure in the same direction. In consequence, a supramolecular crystal structure is generated, with all the beta-strands of the domain-swapped dimers being perpendicular to one crystallographic direction. This observation is relevant to amyloid aggregation of HCC, as X-ray diffraction studies of amyloid fibrils show them to have ordered, repeating structure, consistent with the so-called cross-beta structure, in which extended polypeptide chains are perpendicular to the fiber axis and form infinite beta-sheets that are parallel to this axis.

Amyloid↗
PubMed1999

The 5'-flanking sequence and regulatory elements of the cystatin S gene.

The gene encoding rat cystatin S (Cys S), a salivary gland-specific secretory protein, has CAAT and TATA boxes upstream of the inititation codon (Cox and Shaw, 1992), and contains regions that resemble those of other hormonally responsive eukaryotic genes. The 5'-flanking sequence of the rat Cys S gene has a potential CREB/AP-1 binding site (Rupp et al., 1990; Trejo et al., 1992), two potential glucocorticoid responsive elements (GREs, Drouin et al., 1989), and a possible GR/PR (glucocorticoid/progesterone) responsive element (Forman and Samuels, 1990). One of these potential GREs is adjacent to a potential AP-2 binding site, and another is typical of the glucocorticoid and progesterone receptor binding site. In this report, we have identified three regions in the 5'-flanking region of the Cys S gene that are found in salivary gland-specific genes (Ting et al., 1992) with a GT-rich region located between conserved elements II and III. Transfection experiments described in this paper suggest that a 281-bp DNA fragment from the Cys S gene promoter region with conserved elements II and III, the GT-rich region, and a possible GR/PR responsive element contains a negative regulatory element. In addition, our experiments suggest that the GT-rich region by itself is acting as a positive regulatory element.

Animals↗
PubMed1997

Affinity purification and elimination of methionine oxidation in recombinant human cystatin C.

Recombinant human cystatin C (cC), a cysteine protease inhibitor, contained methionine sulfoxide [Met(O)] residues when expressed in Escherichia coli under aerobic conditions or upon allowing osmotic shock solutions from anaerobically grown cultures to warm to room temperature. Oxidation occurred in the periplasmic space or intracellularly during aerobic expression. Both Met14 and Met41 were subject to oxidation, as determined by NMR spectroscopy and mass spectrometry. Oxidation of Met110 was not observed. Growth under anaerobic conditions and modified purification procedures prevented oxidation. Through the use of a new form of affinity purification, cC was purified to > 99% in one step on E-64-papain-Sepharose (E-64 is 1-[N-[(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucyl]amino]-4-g uanidinobutane), with elution with sodium trichloroacetate. The dissociation equilibrium constants (Kd) for the interaction of unoxidized cC, (Met(O)14)cC, and (Met(O)41)cC with S-(N-ethylsuccinimidyl)papain were experimentally identical: 1.8 (+/-0.2) x 10(-7), 1.6 (+/-0.2) x 10(-7), and 1.4 (+/-0.5) x 10(-7) M, respectively. This implies that the structure of the protease-binding region of mono-oxidized cC's was unchanged. The NMR observation of small, localized conformational changes was consistent with this. (Met(O)14)cC and (Met(O)14,Met(O)41)cC eluted earlier upon analytical affinity chromatography.

Chromatography, Affinity↗
PubMed1993

Inhibitory effects of human cystatin C on plum pox potyvirus proteases.

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.

Cystatin C↗
PubMed1991

SstII polymorphic sites in the promoter region of the human cystatin C gene.

By direct sequencing of polymerase chain reaction (PCR) amplified DNA from different individuals, three points mutations have been found in a 220-bp fragment from the promoter region of the human cystatin C gene. The three mutations are all localized within a short segment of 85bp on the same allele. One of the base substitutions results in the generation of a novel SstII restriction site and another in the loss of the commonly occurring SstII restriction site. A PCR-based assay for analysis of the two SstII sites was designed and used to demonstrate Mendelian inheritance of the polymorphism. This SstII restriction fragment lenght polymorphism offers a new probe-independent marker for chromosome 20 linkage studies.

Base Sequence↗
PubMed1993

An Ala/Thr variation in the coding region of the human cystatin C gene (CST3) detected as a SstII polymorphism.

A DNA variation in the coding region of the human cystatin C gene has been detected by direct sequencing. The polymorphism, a G/A transition, leads to an Ala/Thr variation in the penultimate amino acid of the signal peptide. The base substitution results in the loss of a SstII restriction site, thus allowing the design of a rapid polymerase chain reaction assay for analysis of this polymorphism in the population.

Alanine↗
PubMed1992

Cystatin C in the human pancreas and gut: an immunohistochemical study of normal and neoplastic tissues.

The occurrence of immunoreactive cystatin C (CC) in normal and neoplastic cells of the human pancreas and gut was investigated using an indirect streptavidin-biotin method on formaldehyde-fixed and paraffin-embedded tissues. Virtually all pancreatic islet cells and many neuroendocrine cells throughout the gastrointestinal tract showed strong CC immunoreactivity and a granular cytoplasmic staining pattern. All 14 endocrine pancreatic tumours (insulinomas, glucagonomas, gastrinomas and non-producing tumours), as well as 16 of 17 gut carcinoid tumours, were also strongly CC immunoreactive. In addition, non-endocrine epithelial cells of pancreatic ducts and the gastrointestinal mucosa and 20 of the 24 adenocarcinomas from these sites showed weak CC immunoreactivity. Thus, CC cannot be used as a reliable immunohistochemical marker for endocrine gastro-entero-pancreatic tumours despite the fact that the protein is strongly expressed in a majority of such tumours.

Adenoma↗
PubMed1993

Abnormal distribution of cathepsin proteinases and endogenous inhibitors (cystatins) in the hippocampus of patients with Alzheimer's disease, parkinsonism-dementia complex on Guam, and senile dementia and in the aged.

The immunolocalization of cathepsins B(CB), H and L and cystatins alpha(C alpha) and beta(C beta) were examined in the hippocampus of cases of sporadic Alzheimer's disease (12 cases), parkinsonism-dementia complex on Guam (eight cases), senile dementia of Alzheimer type (two cases), aged subjects with marked senile change (one case) and controls (12 cases, including six normal subjects). CB was lower in most nerve cells in patients than in controls, but markedly increased at the sites of intracellular neurofibrillary tangles (NFTs) and degenerative neurites and/or dendrites in and outside senile plaques (SPs), indicating its close involvement in the metabolisms of various proteins in NFT and SPs. Abundant C alpha and C beta were demonstrated in SP amyloid, suggesting that they are amyloid constituents or co-exist with amyloid. The present study indicated that CB, C alpha and C beta are closely involved in abnormal protein metabolism in NFTs and SP amyloid and suggested that degeneration or denaturation of intracellular proteins, including substrates for proteases and lysosomes, from some acquired cause, results in absolute and/or relative overload for these proteolytic systems, including their inhibitors. This results in incomplete and/or abnormal proteolysis related to NFT and/or amyloid formation.

Adult↗
PubMed2005

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.

Adult↗
PubMed1997

Cystatin C and transthyretin expression in normal and neoplastic tissues of the human brain and pituitary.

The localization of cystatin C (CC) and transthyretin (TTR) synthesis was studied using Northern blot and immunohistochemical methods. Normal brain tissues from all sites studied contained CC mRNA. Immunoreactive CC was present in the choroid plexus epithelial cells, cerebral and cerebellar neurons, astrocytes, ependymal cells, macrophage-like cells of the arachnoid membrane and in neuroendocrine cells of the anterior pituitary lobe. TTR mRNA and TTR were restricted to the choroid plexus. In primary brain tumors, the transcript for CC was found in all 39 tumors examined, while the protein could only be demonstrated in 3/5 choroid plexus papillomas, 8/8 astrocytomas, 7/23 anaplastic astrocytomas and glioblastomas, 1/6 oligodendrogliomas, 1/1 oligoastrocytoma, 1/4 anaplastic oligodendrogliomas, 3/7 ependymomas, 0/1 anaplastic ependymoma, 0/5 primitive neuroectodermal tumors, 0/1 neuroblastoma, 3/11 meningiomas and 16/16 pituitary adenomas. CC cannot be used as a marker for any specific brain tumor type but the fact that the protein could be demonstrated more frequently in astrocytomas than in their more malignant counterparts suggests that the cellular production and secretion of CC changes with the malignant progression of these tumors. TTR mRNA and TTR were present only in the choroid plexus papillomas, indicating that TTR synthesis is mainly restricted to such brain neoplasms.

Blotting, Northern↗
PubMed2002

Impact of age on reference values for serum concentration of cystatin C in children.

Recently, cystatin C (cyst C) was proposed for the assessment of glomerular filtration rate, being more accurate than creatinine determination. Reference intervals for cyst C do not vary with age and sex, like creatinine values. Elevated values of cyst C were reported for pre- and full-term infants. Nevertheless, the age cut-off for stable cyst C values i.e., age independence, remains under discussion. Therefore, we conducted a prospective study in 98 healthy children, 51 being under 18 months of age. Cyst C was determined by the nephelometric method. The infants under the age of 18 months had a higher mean serum cyst C value (0.94 +/- 0.24 mg/l) than the older children (0.65 +/- 0.19 mg/l). There was a negative correlation between age and cyst C in the infant group under the age of 18 months (r(2)=0.631, P<0.01). Our results indicate that mean serum cyst C is higher in infants than older children; the age cut-off appears over the age of 1 year of life, presumably reflecting kidney maturation. Our study does not allow accurate assessment of the age cut-off at 18 months or 36 months.

Aging↗
PubMed2004

Cystatin C is a suitable marker of glomerular function in children with cancer.

Antineoplastic chemotherapy is associated with nephrotoxic side effects. Data on nephrotoxicity in childhood cancer are scanty, in part because of the difficulties in obtaining reliable markers of glomerular function. We used serum cystatin C (cysC) to assess glomerular function. CysC was compared with serum creatinine concentration (S(Cr)), the endogenous creatinine clearence ( C(Cr)), and the calculated Counahan formula ( C(Counahan)) in children with leukemia and solid tumors. CysC was measured by particle-enhanced immunoturbidimetric assay. Serum and urinary creatinine concentrations were determined by the Jaffé method. Samples were obtained from 258 children, including 92 receiving anticancer chemotherapy, 108 long-term survivors, 40 children without any renal disease, and 18 patients with chronic renal insufficiency. CysC of patients on current chemotherapy was assessed both before and after treatment. Significant correlations were found between cysC and S(Cr) and between 1/cysC and C( Counahan). CysC increased significantly after cisplatin, methotrexate, cyclophosphamide, ifosfamide, and multimodality treatment. Our results suggest that cysC measurement can be used to characterize glomerular function in children with cancer.

Adolescent↗
PubMed2006

GFR is better estimated by considering both serum cystatin C and creatinine levels.

Serum cystatin C (cysC) is a potential marker of the glomerular filtration rate (GFR) that has generated conflicting reports in children. A prospective study was conducted to assess the benefit of considering cysC together with serum creatinine (SCr) and demographic and morphologic characteristics to better estimate the 51Cr-ethylenediaminetetraacetate (EDTA) clearance (CL), i.e., the GFR. Plasma 51Cr-EDTA data from 100 children or young adults (range: 1.4-22.8 years old) were analyzed according to the population pharmacokinetic approach by using the nonlinear mixed effects model (NONMEM) program. The actual CL was compared to the CL predicted according to different covariate equations. The best covariate equation (+/-95% confidence interval) was: GFR (ml/min)=63.2(+/-3.4) . [(SCr (microM)/96)(-0.35 (+/-0.20))] . [(cysC (mg/l)/1.2)(-0.56 (+/-0.19))] . [(body weight (kg)/45)(0.30 (+/-0.17))] . [age (years)/14)(0.40 (+/-0.16))]. This equation was associated with a less biased and more precise estimation than the Schwartz equation. CysC improves the estimation of the GFR in children if considered with other covariates within the mathematical formula.

Adolescent↗
PubMed1999

Diagnostic sensitivity of serum cystatin for impaired glomerular filtration rate.

Recently, the reciprocal of cystatin C (Cys-C), a non-glycosylated 13-kilodalton protein that is produced by all investigated nucleated cells, was found to correlate closely with glomerular filtration rate (GFR). In order to determine the diagnostic validity in children for the detection of impaired GFR, venous blood samples from 381 children (aged 1.7-18 years) with various renal pathology referred for 51Cr-EDTA clearance investigations were obtained for measurement of Cys-C as well as beta2-microglobulin (beta2-MG) and serum creatinine. Two hundred and sixteen children with clearance values >90 ml/min per 1.73 m2 constituted a control group, with a normal GFR. In the control group, Cys-C values were normally distributed with a mean of 0.94+/-0.27 mg/l and an upper reference limit (97.5th percentile) of 1.47 mg/l. In all children, there was a positive correlation between 51Cr-EDTA clearance and the reciprocal of Cys-C (r=0.64, P<0.0001), beta2-MG (r=0.59, P<0.0001), creatinine (r=0.55, P<0.0001), and the height/creatinine ratio (r=0.73, P<0.0001). Receiver-operating characteristics analysis showed that there were no significant differences between these three parameters for discriminating between patients with normal and reduced GFR, although there was a tendency towards the best diagnostic sensitivity of the GFR estimate according to the Schwartz formula. We conclude that for the detection of mildly impaired GFR, a full clearance study cannot be replaced by measurement of serum Cys-C or beta2-MG concentrations.

Adolescent↗
PubMed2006

Cystatin C versus creatinine as a marker of glomerular filtration rate in the newborn.

AIM: Serum cystatin C (cysC) has been proposed as a promising endogenous marker of glomerular filtration rate (GFR) in adults and children. The aim of this study was to determine the reference values of cysC at birth and three days later in comparison with creatinine (Cr) and Schwartz's estimated clearance. PATIENTS AND METHODS: 75 newborns (42 boys, 33 girls) were enrolled in the study. The gestational age ranged from 34 to 41 weeks, and the birth weight from 2070 to 4410 g. Blood samples were taken from the umbilical cord at birth and from a peripheral vein three days after birth. CysC and Cr were measured in all serum samples and values analyzed in different subgroups of neonates according to sex, gestational age, birth weight, umbilical blood pH, the influence of bilirubin, hemoglobin and hydration state. The Mann-Whitney U-test and Wilcoxon's analysis were used. RESULTS: At birth, serum cysC values ranged from 1.38 to 3.23 mg/l, not significantly decreasing after 3 days of life. Cr levels, determined simultaneously at birth, ranged from 34 to 99 mumol/l and were also not significantly different from day 3 levels. Both CysC and Cr levels were independent of sex, gestational age, birth weight, bilirubin levels and hydration state. CysC correlated positively only with the hemoglobin level (r = 0.28, P = 0.01) and negatively with cord blood pH (r = -0.40, P = 0.001), similarly to Cr. Significant correlation was found between cysC and Cr in umbilical cord blood (r = 0.30, P = 0.006) and day 3 blood samples (r = 0.37, P = 0.001). No correlation was found between 1/cysC and Schwartz GFR in cord blood (r = 0.18, P = 0.18), but correlation became significant in day 3 blood samples (r = 0.27, P = 0.02). CONCLUSION: This study suggests that cysC is not more sensitive than Cr as a marker of GFR in the newborn.

Biomarkers↗
PubMed2005

Cystatin-C and creatinine as indices of glomerular filtration rate in the immediate follow-up of renal transplant patients.

Serum cystatin-C (cys-C), creatinine (Cr), C-reactive protein (CRP) and amyloid A have been shown to provide useful information for renal function following transplantation. In this study, we wanted to evaluate the impact of these parameters as markers of the glomerular filtration rate (GFR) on the third and seventh days of the post-transplantation period. Cys-C was determined by the particle-enhanced immunoturbidimetric assay, and serum amyloid A (SAA) by the sandwich-enzyme immunoassay kit. Cr and CRP concentrations were measured by the Cobas Integra 400 autoanalyser. The patients (n=35) were followed with daily repetitive measurements of serum Cr and urine output per hour, and with Doppler ultrasonography against the risk of rejection. Statistical evaluations were made using the ANOVA and Pearson's test. Serum cys-C and Cr levels on both the 3rd and 7th days after transplantation were lower than those of pretransplantation values (P<0.001). The Cr/cys-C ratio was decreased on the 3rd day of the post-transplantation period, and kept declining on the 7th day. This ratio was high only in the patient with an acute rejection episode. None of the patients with high pretransplant CRP levels had a rejection episode during a six-month follow-up. SAA concentrations were found to be higher than the pretransplant values in the early post-transplant period. Cys-C had good sensitivity to estimate the renal function in the very early period of transplantation, but its value as a marker of GFR was decreased at the end of first week. As none of the 34 patients had a rejection episode, the observed rise in SAA and CRP levels is not specific to rejection.

Adolescent↗
PubMed1991

Inactivation of human cystatin C and kininogen by human cathepsin D.

A papain inhibitor of 22 kDa was isolated from human placenta and shown to be identical to residues Cys246-Leu373 of the third domain of human kininogen. This kininogen domain and recombinant human cystatin C were inactivated by peptide bond cleavages at hydrophobic amino acid residues due to the action of cathepsin D. These results further support the proposed role of cathepsin D in the regulation of cysteine proteinase activity.

Amino Acid Sequence↗