Vito Turk

..Some of the features and roles of their structures, specificity, regulation and physiology are discussed...

..The levels of some stefins and cystatins in tissue and body fluids can serve as relatively reliable markers for a variety of diseases. In this review we summarize present knowledge about cystatins and their role in some diseases...

..Moreover, this study shows that a broad-spectrum cysteine cathepsin inhibitor effectively blocks several stages of tumorigenesis in the RIP1-Tag2 transgenic mouse model, offering new therapeutic opportunities in cancer treatment...

..Its expression, restricted to immune cells suggests a role in phagocytosis and the regulation of immune response...

..They also bound, similarly to prefibrillar aggregates, to the plasma membrane and became internalized. Taken together, our results confirm the importance of membrane interaction and perforation in the phenomenon of cytotoxicity...

..Moreover, XIAP (X-chromosome-linked inhibitor of apoptosis) was also found to be a target of cysteine cathepsins, suggesting that cathepsins can mediate caspase-dependent apoptosis also downstream of mitochondria...

..Because procathepsin B and GAGs often co-localize in vivo, we propose that GAGs may play a physiological role in the activation of procathepsin B...

..Thus, MAGI-1 cleavage appears to be an important step in the disassembly of cell-cell contacts during apoptosis...

..Secondly, the prolonged first loop of the domain occupies a position near the catalytic cysteine residue in a more substrate-like manner, enabling cleavage of the Gly22-Ala23 bond...

..In contrast, thyropins were relatively inefficient in preventing elastinolysis by cysteine cathepsins...

..The propeptide thus controls dimerization, as well as activation, of lysosomal dipeptidase...

..Samples were examined by transmission electron microscopy. Fibrils of stefin B were strongly labelled using polyclonal antibody and Protein A gold, whereas no positive reaction was observed with monoclonal antibody A6/2...

..Human StB proved to be a good model system to study amyloid fibril formation in vitro and, as we show here, to study protein aggregation in cells...

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..These results show that, besides multiple regulatory molecules, intracellular cathepsin B also contributes to the neovascularization process and should be considered as a potential therapeutic target...

..Similarities to other amyloidogenic proteins and the possible physiological implications of our findings are discussed...

..In contrast, the inhibitory activities of Stfa2-a and Stfa2-b were found to be roughly equivalent for all targets peptidases...

..The G4R mutant exhibited a much longer lag phase than the wild type, with the accumulation of prefibrillar aggregates. Implications for pathology in view of the higher toxicity of prefibrillar aggregates to cells are discussed...

..We conclude that granule-bound cathepsins are essential for processing perforin to its active form, and that CatL is an important, but not exclusive, participant in this process...

..These results thus indicate that the cathepsin H mini chain is essential for the aminopeptidase activity of the enzyme but has only a minor effect on the inhibition by cystatins...

..However, these interactions may occur extracellularly in lymph, as suggested by the large excess of CyC over secreted CatS, -L, and -H, and they may facilitate DC migration to lymph nodes...

..We conclude that sensitization to apoptosis induced by STS in thymocytes of stefin B-deficient and wild-type mice is not dependent on cathepsin inhibition by stefin B...

..Thus, both enzymes were expressed and biochemically characterized. The enzymes exhibited similar biochemical properties, indicating that cathepsin B transgenic mouse models could be useful for studying its role in human pathologies...

..It also co-immunoprecipitates with the APP fragment containing the Abeta epitope. Thus, stefin B is another APP/Abeta-binding protein in vitro and likely in cells...

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..This chapter reviews the methods used to study lysosomes and lysosomal proteases...

..In addition to proteases, interleukin-6 was detected at significant levels in most samples, suggesting that proinflammatory cytokines might be in-volved in the stimulation of expression of these proteases during inflammation...

..5. This novel property of procathepsin S may have implications in pathological conditions associated with the appearance of active cathepsins outside lysosomes...

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..Incubation of full-length Bid treated with cathepsins B, H, L, and S resulted in rapid cytochrome c release from isolated mitochondria. Thus, Bid may be an important mediator of apoptosis induced by lysosomal disruption...

..Their identification is among the first pieces of information about the action of the SMOCs on molecular level and opens new possibilities for future research aimed towards elucidating the physiological roles of these versatile proteins...

..The finding that cystatin F was not colocalized with cystatin C suggests distinct functions for these two cysteine protease inhibitors in U937 cells...

..When overexpressed in MDCK cells, both N- and C-terminal MAGI-1 caspase cleavage products exhibited minor proapoptotic activity, although their role in apoptosis is probably more passive...

..Moreover, Bid cleavage was found to be diminished in cathepsin B-deficient cells. These results suggest that cysteine cathepsins have no active role in Fas/CD95 apoptosis...

..In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome...

..This further suggests that lysosomes and lysosomal cathepsins have a dual role in cell death. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome...

..Special emphasis is given to the newly discovered role of lysosomal cathepsins in apoptotic pathways...

..From the latter, all domain interactors up to level 4 were retrieved, thus displaying a more comprehensive representation of the KKS-RAS structural network...

..Additionally, we show that TSH, insulin, and/or somatostatin induce up-regulation of N-acetylglucosaminyltransferase 1, the enzyme responsible for the initiation of biosynthesis of hybrid and complex N-glycosylation of proteins...

..Our aim has been to obtain a comprehensive insight into their origin, distribution, diversity, evolution and classification in Eukaryota, Bacteria and Archaea...

..7 nM). Stefin A inhibited cathepsin F slowly (kass=1.6 x 10(5) M(-1) s(-1)) and with a lower affinity (Ki=25 nM). These data suggest that cathepsin F differs from other related endopeptidases by considerably weaker inhibition by stefins...

..The cleavage points with cathepsins B and L on the second and the fourth domains were determined. The possible reasons for degradation are discussed...

..We classify these as: (a) templating and nucleation; (b) linear, colloid-like assembly of spherical oligomers; and (c) domain-swapping. In this review, we stress the role of domain-swapping and discuss the role of proline switches...

..Further experiments will be required to complete the characterization of these proteins and elucidate their role in the parasite...

..Once in the cytosol, cathepsins can trigger cell death by different mechanisms. Here we discuss the different signaling pathways used by lysosomal proteases to trigger apoptosis and their potential role in physiological processes...

..Our results show that intracellular and extracellular cathepsin B activity contribute to in vitro invasion of MCF-10A neoT cells and suggest that inhibitors capable of impairing both fractions have a potential as new anticancer drugs...

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..In addition, we show that the interaction of eq d-2 with cathepsin D results in conformational changes, which is not the case for the eq d-1/papain interaction...

..Similarly, links with other signalling systems are not well established. Herein, we will highlight current challenges in protease research...

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..However, there is increasing evidence that lysosomal proteases are also involved in apoptosis. In this review various lysosomal proteases and their potential contribution to propagation of apoptosis are discussed...

..The finding that human stefin B, in contrast to the homologue stefin A, forms amyloid fibrils rather easily should promote further studies of the protein's behaviour in vivo, and/or as a model system for fibrillogenesis...