Turk Vito, Stoka Veronika, Turk Dusan
J. Stefan Institute, Dept. of Biochemistry, Molecular and Structural Biology, SI-1000 Ljubljana, Slovenia.
Front Biosci. 2008 May 1;13:5406-20. doi: 10.2741/3089.
The cystatin superfamily comprises a large group of the cystatin domain containing proteins, present in a wide variety of organisms, including humans. Cystatin inhibitory activity is vital for the delicate regulation of normal physiological processes by limiting the potentially highly destructive activity of their target proteases such as the papain (C1) family, including cysteine cathepsins. Some of the cystatins also inhibit the legumain (C13) family of enzymes. Failures in biological mechanisms controlling protease activities result in many diseases such as neurodegeneration, cardiovascular diseases, osteoporosis, arthritis, and cancer. Cystatins have been classified into three types: the stefins, the cystatins and the kininogens, although other cystatin-related proteins, such as CRES proteins, are emerging. The stefins are mainly intracellular proteins, whereas the cystatins and the kininogens are extracellular. The cystatins are tight binding and reversible inhibitors. The basic mechanism of interaction between cystatins and their target proteases has been established, based mainly on the crystal structures of various cathepsins, stefins and cystatins and their enzyme-inhibitor complexes. Cystatins, as rather non-selective inhibitors, discriminate only slightly between endo- and exopeptidases. They are also prone to form amyloids. 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.
胱抑素超家族由一大类含有胱抑素结构域的蛋白质组成，存在于包括人类在内的多种生物体中。胱抑素的抑制活性对于通过限制其靶蛋白酶（如木瓜蛋白酶（C1）家族，包括半胱氨酸组织蛋白酶）潜在的高度破坏活性来精细调节正常生理过程至关重要。一些胱抑素还抑制木瓜凝乳蛋白酶（C13）家族的酶。控制蛋白酶活性的生物学机制失效会导致许多疾病，如神经退行性疾病、心血管疾病、骨质疏松症、关节炎和癌症。胱抑素已被分为三种类型：丝抑素、胱抑素和激肽原，尽管其他与胱抑素相关的蛋白质，如CRES蛋白，也不断出现。丝抑素主要是细胞内蛋白质，而胱抑素和激肽原是细胞外蛋白质。胱抑素是紧密结合且可逆的抑制剂。基于各种组织蛋白酶、丝抑素和胱抑素及其酶 - 抑制剂复合物的晶体结构，已确定了胱抑素与其靶蛋白酶之间相互作用的基本机制。胱抑素作为相当非选择性的抑制剂，对内肽酶和外肽酶的区分仅略有不同。它们也易于形成淀粉样蛋白。组织和体液中一些丝抑素和胱抑素的水平可作为多种疾病相对可靠的标志物。在本综述中，我们总结了关于胱抑素及其在某些疾病中作用的现有知识。
