Cystatins

To this list of protein misfolding diseases can be added rare familial amyloidoses in which the mutated proteins have the classic amyloid fibril congophilic birefringence and cross-(3-sheet structure (Table 3). Many of these deposits have an impact on the central nervous system (TTR, cystatin, lysozyme) as well as on other organ systems. A newly described disease, familial British dementia, is associated with the deposition of Abri, a 34 amino acid, 4 kDa peptide cleaved from a 277 amino acid precursor sequence, the last 10 amino acids of which are not normally translated [52]. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is... 

The N-terminal sequence of one peptide from the 35 kDa zone of H-gal-GP showed some homology to cathepsin B-like cysteine proteases. Molecular cloning has also identified a thrombospondin homologue associated with the diffusely staining region between zones A and B, a galectin associated with zone D (Newlands et al., 1999) and a low molecular weight (approximately 13 kDa) cysteine protease inhibitor, cystatin. 

Unverricht-Lungborg disease Autosomal recessive Cystatin B... 

Huaux, F. et al., Lung Toxicity of Hard Metal Particles and Production of Interleukin-1, Tumor Necrosis Factor-a, Fibronectin, and Cystatin-c by Lung Phagocytes, Toxicol. Appl. Pharmacol., 132, 53, 1995. 

AP and tau, 6-2 microglobulin Immunoglobulin light chain Serum amyloid A (SAA) Transthyretin (TTR) Apolipoprotein A-l Cystatin A Gelsolin... 

Two models have been proposed for how this dimeric structure may relate to the structure of cystatin C in the fibril. The first (Janowski et at, 2001) proposes that run-away domain swapping (like that shown in Fig. 11C) can account for the assembly and stability of the fibril. In this model, one monomer would swap /(I-a 1-/12 into a second monomer, the second would swap its /(I-a 1-/12 into a third, and so on. The second model (Staniforth et al., 2001) proposes a direct stacking of domain-swapped dimers, where /i5 of each subunit of the dimer would interact with /(I of a subunit of the adjacent dimer. In this way, the dimers would stack to form continuous /1-sheets. Both models arrange the /(-sheets parallel to the fibril axis with component /(-strands perpendicular to the axis, as in a cross-/ structure, although no diffraction pattern has been reported for cystatin fibrils. 

A later study by Nilsson et al. (2004) examined the role of 3D domain swapping in cystatin C fibril formation. By engineering in a disulfide bond to prevent formation of the domain-swapped dimer, the authors were able to reduce fibril formation by 80%. These results suggest that the 3D domain swapping seen in the dimer cannot uniquely account for cystatin C fibril formation either fibril formation is achieved via a different mechanism or multiple pathways are possible, of which 3D domain swapping is one (Nilsson et al., 2004). 

Ekiel, I., and Abrahamson, M. (1996). Folding-related dimerization of human cystatin C. J. Biol. Chem. 271, 1314-1321. 

Janowski, R., Kozak, M., Jankowska, E., Grzonka, Z., Grubb, A., Abrahamson, M., and Jaskolski, M. (2001). Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat. Struct. Biol. 8, 316-320. 

Nilsson, M., Wang, X., Rodziewicz-Motowidlo, S., Janowski, R., Lindstrom, V., Onnerfjord, P., Westermark, G., Grzonka, Z., Jaskolski, M., and Grubb, A. (2004). Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C Use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C.J. Biol. Chem. 279, 24236- 24245. 

Olafsson, I., and Grubb, A. (2000). Hereditary cystatin C amyloid angiopathy. Amyloid 7, 70-79. 

Staniforth, R. A., Giannini, S., Higgins, L. D., Conroy, M. J., Hounslow, A. M.,Jerala, R., Craven, C. J., and Waltho, J. P. (2001). Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. EMBO J. 20, 4774-4781. 

Serum creatinine is not a good measure of renal function in elderly because muscle mass is reduced and the production of creatinine is thus reduced. Estimation of GFR based on serum creatinine is therefore not accurate enough in the elderly (Baracskay et al. 1997). Creatinine clearance should be used instead. Another possibility is measurement of cystatin C in plasma. The rate of production of cystatin C is relatively constant so it seems to be a more reliable estimation of GFR also in older adults. 

Stefin or cystatin (cysteine protease inhibitor) Homo sapiens 95 (dimer form) 358-363... 

Cystatin C (Formerly Post-y-globulin, y-Trace Protein). Cystatin C is a new parameter in a spinal fluid and serum (plasma), originating from glial elements and belonging to so-called trace proteins. Its increasein CSF is considered to be a marker of tissue destruction. Assessment of cystatin C in serum (plasma) is a marker of renal glomerular filtration. 

A straightforward approach is to hunt for short polypeptides that meet the specificity requirement of an enzyme but which, because of peculiarities of the sequence, are acted upon very slowly. Such a peptide may contain unusual or chemically modified amino acids. For example, the peptide Thr-Pro-nVal-NMeLeu-Tyr-Thr (nVal=norvaline NMeLeu = N-methylleucine) is a very slow elastase substrate whose binding can be studied by X-ray diffraction and NMR spectroscopy.6 Thiol proteases are inhibited by succinyl-Gln-Val-Val-Ala-Ala-p-nitroanilide, which includes a sequence common to a number of naturally occurring peptide inhibitors called cystatins.f They are found in various animal tissues where they inhibit cysteine proteases. 

Cyclohexanedione, reaction with guanidinium groups, 126 Cyclophilin 488 human 488s D-Cycloserine 739s Cyclosporin 488, 488s p Cylinders 65, 66, 686 Cystathionine, 746s formation 746 Cystathionine p lyase 742 Cystathionine p-synthase 744 Cystathionine y-synthase 743, 746 Cystatins 622, 629... 

Epilepsy may arise also from defects in a GABA transporter1145 or receptor.1146 One form of epilepsy is a triple-repeat disease of cystatin B (Table 26-4). Mutation in potassium channels,1147 glutamate receptors,1148 absence of neuropeptide Y,1149 and absence of L-isoaspartyl / D-aspartyl O-methyltransferase (Box 12-A)1150 have all been associated with epilepsy. 

Figure B3.1.1 A 15% SDS-polyacrylamide gel stained with Coomassie brilliant blue. Protein samples were assayed for the purification of a proteinase, cathepsin L, from fish muscle according to the method of Seymour et al. (1994). Lane 1, purified cathepsin L after butyl-Sepharose chromatography. Lane 2, cathepsin L complex with a cystatin-like proteinase inhibitor after butyl-Sepharose chromatography. Lane 3, sarcoplasmic fish muscle extract after heat treatment and ammonium sulfate precipitation. Lane 4, sarcoplasmic fish muscle extract. Lanes M, low-molecular-weight standards aprotinin (Mr 6,500), a-lactalbumin (Mr 14,200), trypsin inhibitor (Mr 20,000), trypsinogen (Mr 24,000), carbonic anhydrase (Mr 29,000), gylceraldehyde-3-phosphate dehydrogenase (Mr 36,000), ovalbumin (Mr 45,000), and albumin (Mr 66,000) in order shown from bottom of gel. Lane 1 contains 4 pg protein lanes 2 to 4 each contain 7 pg protein.

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