| Name | Inhibitor family I25 (cystatin family) |
|---|
| Family type peptidase | I25.001 - cystatin A (Homo sapiens), MEROPS Accession MER0018158 (inhibitor unit: 1-98) |
| Content of family | Inhibitor family I25 contains inhibitors primarily of the papain-like cysteine peptidases in family C1. |
| History |
Identifier created: MEROPS 6.1 (10 January 2003)
In 1968, the presence in chicken egg-white of an inhibitor of ficin and papain was reported (Fossum & Whitaker, 1968). During the 1970"s the egg-white inhibitor (I25.011) was further characterised in the laboratories of J. R. Whitaker and H. Keilova (see Literature), and in 1981 the name 'cystatin' was proposed for it (Barrett, 1981). Not long after, it became clear that generally similar inhibitors are present also in mammalian tissues, and that these include both intracellular and extracellular (secreted) forms. When amino acid sequences showed that these inhibitors were homologous, the cystatin family was born. There are four subfamilies: subfamily A contains the cytoplasmic cystatins A (I25.001) and B (I25.003), whereas subfamilies B and D contain homologues like cystatin C (I25.004) and sarcocystatin (I25.013), respectively, that are secreted. Also secreted are the larger molecules of the homologues in subfamily C, of which kininogen (LI25-002) is an example. |
| Peptidases inhibited | Cystatins in subfamily I25A inhibit peptidases of family C1 (Green et al., 1984). The inhibitors in subfamily I25B act mostly on peptidases of family C1 (Bode et al., 1988), but some also inhibit legumain (in family C13, clan CD) through a second reactive site (Alvarez-Fernandez et al., 1999). One of the cystatin domains (I25.016) in kininogen (LI25-002) inhibits calpain (C02.002) (Salvesen et al., 1986). The inhibitors in subfamily I25C affect peptidases of families S8 (Cornwall et al., 2003) and M12 (Valente et al., 2001), but not family C1. |
| Mechanism of inhibition | From the crystallography of uncomplexed ovocystatin (I25.011) it was suggested that the inhibitor inserts a wedge-shaped edge into the reactive site cleft of a papain-like enzyme. The wedge is formed from three separate parts of the polypeptide chain: two hairpin loops (Gln53–Gly57, Pro103–Trp104) and the N-terminal Gly9–Ala10. This proposal was confirmed by the structure of a complex of cystatin B (I25.002) with carboxymethylated papain (C01.001) (Stubbs et al., 1990) and that of cystatin A (I25.001) with cathepsin H (C01.040) (Jenko et al., 2003). The involvement of the N-terminal segment of the inhibitor (interacting with the unprimed specificity sites) accounts for a dramatic loss of inhibitory potency that commonly occurs when residues are trimmed from the N-terminus of a cystatin (Abrahamson et al., 1987).
Cystatin C (I25.004) inhibits legumain (C13.004) through a second, independent, reactive site probably involving Asn39 (Alvarez-Fernandez et al., 1999). |
| Molecular structure | The protein fold characteristic of the cystatin family has been established by crystal structures of ovocystatin, cystatin A, cystatin B, cystatin C (I25.004) and cystatin D (I25.005), as well as several solution structures. The inhibitor units in subfamily I25A contain no disulfides, whereas those in the other subfamilies typically contain two disulfide loops. In addition to the majority of simple inhibitors, the family also contains compound inhibitors with 2 (e.g. LI25-005), 3 (e.g. LI25-006) or 8 (e.g. LI25-001) inhibitor units (Rawlings et al., 2004). |
| Clan | IH |
| Biological functions | In plants, the phytocystatins (I25.014) probably contribute to the defences of the plant against predatory insects, inhibiting the digestion of plant proteins in the insect gut. In animals, it is likely that they play a part in the regulation of activity of endogenous lysosomal cysteine peptidases both inside and outside cells. |
| Pharmaceutical and biotech relevance | A mutation in the human cystatin C gene causes a rare form of hereditary brain haemorrhage (Gerhartz & Abrahamson, 2002). There is much interest in the potential of transgenic phytocystatins for the protection of plants against insect pests (e.g. Atkinson et al., 2004). |
| Reviews | An early review was provided by Barrett et al. (1986) and a more recent one is that of Abrahamson (1994).
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| Statistics for family I25 | Sequences: | 4321 |
| Identifiers: | 70 |
| Identifiers with PDB entries: | 17 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Inhibitors and Homologues |
MEROPS ID |
Structure |
| cystatin C | I25.004 | Yes |
| cystatin D | I25.005 | Yes |
| cystatin 6 | I25.006 | Yes |
| cystatin F | I25.007 | Yes |
| cystatin S | I25.008 | - |
| cystatin SA | I25.009 | - |
| cystatin SN | I25.010 | - |
| ovocystatin | I25.011 | Yes |
| snake venom cystatin (Bitis sp.) | I25.012 | - |
| phytocystatin | I25.014 | Yes |
| potato multicystatin inhibitor unit 1 | I25.015 | - |
| kininogen inhibitor unit 2 | I25.016 | - |
| kininogen inhibitor unit 3 | I25.017 | Yes |
| T-kininogen inhibitor unit 2 | I25.018 | - |
| T-kininogen inhibitor unit 3 | I25.019 | - |
| cystatin-related epididymal spermatogenic protein | I25.027 | - |
| oryzacystatin II | I25.028 | - |
| sunflower multicystatin inhibitor unit 1 | I25.029 | - |
| papaya cystatin | I25.030 | - |
| onchocystatin | I25.031 | - |
| CPI-2a cystatin-like inhibitor (Caenorhabditis elegans) | I25.032 | - |
| phytocystatin (Actinidia sp.) | I25.033 | - |
| potato multicystatin inhibitor unit 2 | I25.034 | Yes |
| potato multicystatin inhibitor unit 3 | I25.035 | - |
| potato multicystatin inhibitor unit 4 | I25.036 | - |
| potato multicystatin inhibitor unit 5 | I25.037 | - |
| potato multicystatin inhibitor unit 6 | I25.038 | - |
| potato multicystatin inhibitor unit 7 | I25.039 | - |
| potato multicystatin inhibitor unit 8 | I25.040 | Yes |
| chum salmon cystatin (Oncorhynchus keta) | I25.041 | - |
| cystatin Bm-CPI-1 (Brugia malayi) | I25.043 | - |
| cystatin Bm-CPI-2 (Brugia malayi) | I25.044 | - |
| caneCPI cystatin (Saccharum sp.) | I25.045 | - |
| EPIC1 (Phytophthora infestans) | I25.047 | - |
| EPIC2B (Phytophthora infestans) | I25.048 | - |
| sialostatin L (Ixodes scapularis) | I25.049 | Yes |
| cystatin 4 (Triticum aestivum) | I25.050 | - |
| cystatin Hv-CPI1 (Hordeum vulgare) | I25.051 | Yes |
| cystatin Hv-CPI-2 (Hordeum vulgare) | I25.052 | Yes |
| cystatin Hv-CPI3 (Hordeum vulgare) | I25.053 | - |
| cystatin Hv-CPI5 (Hordeum vulgare) | I25.054 | - |
| cystatin Hv-CPI6 (Hordeum vulgare) | I25.055 | - |
| cystatin Hv-CPI8 (Hordeum vulgare) | I25.056 | - |
| cystatin Hv-CPI9 (Hordeum vulgare) | I25.057 | - |
| cystatin Hv-CPI10 (Hordeum vulgare) | I25.058 | - |
| cystatin Hv-CPI11 (Hordeum vulgare) | I25.059 | - |
| cystatin Hv-CPI13 (Hordeum vulgare) | I25.060 | - |
| cystatin AtCys2 (Arabidopsis thaliana) | I25.062 | - |
| cystatin CC9 (Zea mays) | I25.063 | - |
| cystatin 9 (Homo sapiens) | I25.065 | - |
| sunflower multicystatin inhibitor unit 2 | I25.958 | - |
| sunflower multicystatin inhibitor unit 3 | I25.959 | - |
| Subfamily I25B non-peptidase homologues | non-peptidase homologue | - |
| Subfamily I25B unassigned peptidases | unassigned | Yes |
