Friends and relations of the cystatin superfamily—new members and their evolution

Abstract

The cystatin "superfamily" encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never aquired this inhibitory activity. In recent years, several new members of the superfamily have been characterized, including proteins from insects and plants. Based on partial amino acid homology, new members, such as the invariant chain (Ii), and the transforming growth factor+ receptor type I1 (TGF-/3 receptor 11) may, in fact, represent members of an emerging family within the superfamily that may have used some common building blocks to form functionally diverse proteins. Cystatin superfamily members have been found throughout evolution and members of each family of the superfamily are present in mammals today. In this review, the new and older, established members of the family are arranged into a possible evolutionary order, based on sequence homology and functional similarities.Keywords: cystatins; cysteine protease inhibitors; evolution; fetuins; kininogens; TGF-/3 receptor I1The concept of a cystatin "superfamily" emerged in the early 1980s, precipitated by an observation that multiple cystatin-like sequences were present in the kininogens and that the stefins were related to both the cystatins and the repeats in the kininogens (Ohkubo et al., 1984). The cystatins are a family of cysteine protease inhibitors with homology to chicken cystatin (Barrett, 1981). Cystatins typically comprise = 1 15 amino acids, are largely acidic, contain four conserved cysteine residues known to form two disulfide bonds (Grubb et a]., 1984), may be glycosylated and/or phosphorylated, and contain a series of conserved residues, most notably the "QVVAG' sequence (reviewed in Rawlings & Barrett, 1990;Turk & Bode, 1991).Protein, cDNA, and genomic sequences of several cystatins have since been reported (e.g., Tsai et al., 1996; reviewed in Rawlings & Barrett, 1990;Turk & Bode, 1991). Their structural genes comprise three exons of characteristic size (e.g., Huh et al., 1995) (Fig. I), and a cluster of these genes is located on human chromosome 20 (e.g., Thiesse et al., 1994) although cystatin genes are also found on other chromosomes (e.g., Pennachio et al., 1996).Cystatin-like sequences identified in the kininogens (Ohkubo et al., 1984) were found to be present as sequence duplications. Subsequently, it was proposed that there were three cystatin-like repeats in the kininogen sequence, the amino terminal repeat being Reprint requests to: K.M Dziegielewska, Department of Anatomy and Physiology, University of Tasmania, GPO Box 252-24, Hobart, Tasmania 7001, Australia. less conserved (Salvesen et al., 1986). This threefold repeat is reflected in the triplicated gene structure (Kitamura et al., 1985). which has been shown to be common to the kininogens (e.g., Cole & Schreiber, 1992). Each of the three cystatin repeats is encoded by three exons of characteristic size (e.g., Cole & Schreiber, 1992).Thus, by the late 1980s the superfa...

Characterization of Solanum tuberosum Multicystatin and Its Structural comparison with Other Cystatins

“…The larger type II cystatin family (;13 kD) consists of proteins with two conserved disulfide bonds and includes chicken egg white (CEW) cystatin and human cystatin C, D, and F. The largest family of cystatins, the type III cystatin family (;68 to 120 kD), includes kininogen, which is made up of several glycosylated type II cystatin-like domains (reviewed in Rawlings and Barrett, 1990;Turk and Bode, 1991). More recently, several other types of cystatin-like inhibitor proteins have been characterized (Brown and Dziegielewska, 1997). Even though sequence similarity between PMC and the type I cystatin family is low, an individual domain of PMC could belong to the type I cystatin family because they both lack disulfide bonds.…”

Molecular Characterization and Expression Pattern of Fetuin-B in Gibel Carp (Carassius auratus gibelio)

“…NetPhos 2.0 analysis revealed 25 potential phosphorylation sites (data not shown). The putative signal peptide of 16 amino acids, the fetuin motif signature of 10 amino acids DXLETXCHXL (Olivier et al 2000), and the 12 critical Cs used as a fetuin signature (Brown and Dziegielewska, 1997) were also observed (Fig. 1).…”

“…Fetuin-A was first identified in fetal cow in 1944 (Pedersen 1944). In recent years, fetuin-A homologs have been cloned in sheep, pigs, cows, humans, mice, gerbils, and rats (Auberger et al 1989;Rauth et al 1992;Saunders et al 1994;Goto et al 1997;Brown and Dziegielewska 1997). Fetuin-A has been shown to function in many physiological aspects, such as fatty acid transport (Cayatte et al 1990), regulation of insulin activity and hepatocyte-growth-factor activity (Mathews et al 2002;Ohnishi et al 1997), response to systemic inflammation (Ombrellino et al 2001), and inhibition of unwanted mineralization (Schinke et al 1996;Heiss et al 2003;Schäfer et al 2003).…”

A promising tool for biomolecular nanotechnology - bionanoparticles

“…α-Heremans-Schmid glycoprotein/Fetuin-A (human) or fetuin-A (calf) (Brown et al, 1992) is a plasma protein from the cystatin superfamily of cysteine protease inhibitors with considerable biological importance (Dziegielewska et al, 1990;Brown and Dziegielewska, 1997;Otto and Schirmeister, 1997;Maria et al, 2007). Dialysis patients are prone to vascular and valvular calcifications (ectopic calcification), presumably because of their low fetuin-A serum level (Xie et al, 2005).…”