Cystatins: Biochemical and structural properties, and medical relevance

Abstract

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.

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

“…atherosclerosis, adiposity, angiogenesis, and tumor invasion), making them striking targets for new anti-protease drugs (15,16). Their proteolytic activity is specifically regulated by their natural inhibitors, members of the cystatin superfamily (stefins, cystatins, and kininogens) (17,18), suggesting that an imbalance between Cats and cystatins could be crucial for the breakdown of ECM components. Genetic inhibition of Cat B in a murine BDL (bile duct ligation) model reduced hepatic inflammation, collagen deposition, and fibrogenesis (19).…”

Global secretome analysis identifies novel mediators of bone metastasis

“…Cystatins are cysteine protease inhibitors, with cystatin-C (CST3) potently inhibiting pro-metastatic Cathepsin B [61] and thus being considered to be a potential metastasis suppressor. The salivary cystatins, however, have not been shown to strongly antagonize Cathepsin B [62], and instead have been hypothesized to function in salivary glands as inhibitors of harmful proteinases expressed by pathogens [63]. Additionally, the salivary cystatins have been suggested to have high affinity for hydroxyapatite, the main mineralized component of bone tissue [64].…”

Decreased IL‐10 expression in stefin B‐deficient macrophages is regulated by the MAP kinase and STAT‐3 signaling pathways

“…The cystatins are endogenous, reversible and tight-binding inhibitors of the papain (C1) and legumain (C13) families of the cysteine proteases and have significant similarities in the amino acid sequence and in the protein structure [1,2]. Stefin B (cystatin B) is an endogenous cysteine cathepsin inhibitor localized in the cytosol and nucleus, where it interacts with histones and cathepsin L [3].…”