Abstract
The majority of lysosomal cysteine cathepsins are ubiquitously expressed enzymes. However, some of them differ in their specific cell or tissue distribution and substrate specificity, suggesting their involvement in determining normal cellular processes, as well as pathologies. Their proteolytic activities are potentially harmful if uncontrolled. Therefore, living organisms have developed several regulatory mechanisms such as endogenous protein inhibitors of the cystatin family, including the group of small cytosolic proteins, the stefins. The main focus of this review is stefins of various origins and their properties, structure, and mechanism of interaction with their target enzymes. Furthermore, oligomerization and fibrillogenesis in stefins and/or cystatins provide insights into conformational diseases. The present status of the knowledge in this field and current trends might contribute to identifying novel therapeutic targets and approaches to treat various diseases.
Highlights
The discovery of the lysosome was crucial for understanding intracellular protein degradation processes.[1]
Porcine stefins A and B bind tightly and rapidly to exopeptidase cathepsin H (Ki = 0.02 and 0.07 nM, respectively), stefins D1 and D2 are poorer inhibitors of the same enzyme (Ki = 102–125 nM) and weak inhibitors of cathepsin B (Ki = 335 and 195 nM, respectively), and all four stefins (A, B, D1, and D2) are fast-acting and tight-binding inhibitors to the endopeptidases cathepsins L and S and papain (Ki values ranging 0.01–0.19 nM), as expected.[99]. These results suggest that in addition to the differences in the enzyme active sites, which are used to classify proteases as endo- and exopeptidases, minor specific structural features of the porcine stefins, in particular, play an important role in binding
A similar effect was observed in truncated forms of human cystatin C of the first ten residues[119] and chicken cystatin upon deletion of the first eight residues preceding Gly9.120 In summary, it is evident that some stefin-type parasite inhibitors are strong and tight-binding inhibitors of their endogenous cysteine proteases-cathepsins as well as human and other mammalian cathepsins, suggesting their involvement in the immune regulation and inflammatory diseases.[121,122,123,124,125]
Summary
The discovery of the lysosome was crucial for understanding intracellular protein degradation processes.[1]. A protein inhibitor of cysteine cathepsins was isolated from the sera of patients with Balkan endemic nephropathy, and the first 47 residues of the N-terminal sequence[86] was identical to that of human γ-trace,[87] and the name human cystatin was proposed.[86,88] Soon after, it was renamed human cystatin C.89 These and other accumulated data were of great importance for the nomenclature and classification of the cystatin superfamily, comprising three families.[90] The inhibitor cystatin B/stefin B was isolated from human liver[91] and human spleen,[92] and the resulting sequences of the first 65 residues were identical, strongly suggesting that both inhibitors, isolated from different tissues, are structurally identical proteins.[92] The stefin B dimer was confirmed for the first time from human spleen.[92] Structurally homologous inhibitors to human stefins A and B have been identified and characterized in mammals, such as rats[93,94] and mice.[95] Stefin A,96 stefin B,97 and stefin C98 are found in bovines. Stefins are the smallest among the members of the cystatin family of inhibitors
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