Summary: Cystatin domain
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Cystatin Edit Wikipedia article
|Proteinase inhibitor I25, cystatin|
The cystatins are a family of cysteine protease inhibitors which share a sequence homology and a common tertiary structure of an alpha helix lying on top of an anti-parallel beta strand. The family is subdivided as described below.
Cystatins show similarity to fetuins, kininogens, histidine-rich glycoproteins and cystatin-related proteins. Cystatins mainly inhibit peptidase enzymes (another term for proteases) belonging to peptidase families C1 (papain family) and C13 (legumain family). They are known to mis-fold to form amyloid deposits and are implicated in several diseases.
The cystatin family includes:
- The Type 1 cystatins, which are intracellular and are present in the cytosol of many cell types, but can also appear in body fluids at significant concentrations. They are single-chain polypeptides of about 100 residues, which have neither disulfide bonds nor carbohydrate side-chains. Type 1 cystatins are also known as Stefins (after the Stefan Institute where they were first discovered )
- The Type 2 cystatins, which are mainly extracellular secreted polypeptides are largely acidic, contain four conserved cysteine residues known to form two disulfide bonds, may be glycosylated and/or phosphorylated. They are synthesised with a 19- to 28-residue signal peptide. They are broadly distributed and found in most body fluids.
- The Type 3 cystatins, which are multidomain proteins. The mammalian representatives of this group are the kininogens. There are three different kininogens in mammals: H- (high-molecular-mass, IPR002395) and L- (low-molecular-mass) kininogen, which are found in a number of species, and T-kininogen, which is found only in rats.
- Unclassified cystatins. These are cystatin-like proteins found in a range of organisms: plant phytocystatins, fetuin in mammals, insect cystatins, and a puff adder venom cystatin, which inhibits metalloproteases of the MEROPS peptidase family M12 (astacin/adamalysin). Also, a number of the cystatin-like proteins have been shown to be devoid of inhibitory activity.
- Cystatin C - a novel marker of kidney function.
- ; Salát J, Paesen GC, Rezácová P, Kotsyfakis M, Kovárová Z, Sanda M, Majtán J, Grunclová L, Horká H, Andersen JF, Brynda J, Horn M, Nunn MA, Kopácek P, Kopecký J, Mares M (June 2010). "Crystal structure and functional characterization of an immunomodulatory salivary cystatin from the soft tick Ornithodoros moubata". Biochem. J. 429 (1): 103–12. doi:10.1042/BJ20100280. PMC 3523712. PMID 20545626.; rendered with PyMOL
- Rawlings ND, Barrett AJ (1990). "Evolution of proteins of the cystatin superfamily". J. Mol. Evol. 30 (1): 60–71. doi:10.1007/BF02102453. PMID 2107324.
- Abrahamson M, Alvarez-fernandez M, Nathanson CM (2003). "Cystatins". Biochem. Soc. Symp. (70): 179–199. PMID 14587292.
- Bode W, Turk V (1991). "The cystatins: protein inhibitors of cysteine proteinases". FEBS Lett. 285 (2): 213–219. doi:10.1016/0014-5793(91)80804-C. PMID 1855589.
- Machleidt, W.; Borchart, U.; Fritz, H.; Brzin, J.; Ritonja, A.; Turk, V. (1983). "Protein inhibitors of cysteine proteinases. II. Primary structure of stefin, a cytosolic protein inhibitor of cysteine proteinases from human polymorphonuclear granulocytes". Hoppe-Seyler's Zeitschrift fur physiologische Chemie 364 (11): 1481–1486. doi:10.1515/bchm2.1983.364.2.1481. PMID 6689312.
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Cystatin domain Provide feedback
Very diverse family. Attempts to define separate sub-families failed. Typically, either the N-terminal or C-terminal end is very divergent. But splitting into two domains would make very short families. All members except Q03196 and Q10993 are found. PF00666 are related to this family but have not been included.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000010
Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties.
The cystatins are cysteine proteinase inhibitors belonging to MEROPS inhibitor family I25, clan IH [PUBMED:2107324, PUBMED:14587292, PUBMED:1855589]. They mainly inhibit peptidases belonging to peptidase families C1 (papain family) and C13 (legumain family). The cystatin family includes:
- The Type 1 cystatins, which are intracellular cystatins that are present in the cytosol of many cell types, but can also appear in body fluids at significant concentrations. They are single-chain polypeptides of about 100 residues, which have neither disulphide bonds nor carbohydrate side chains.
- The Type 2 cystatins, which are mainly extracellular secreted polypeptides synthesised with a 19-28 residue signal peptide. They are broadly distributed and found in most body fluids.
- The Type 3 cystatins, which are multidomain proteins. The mammalian representatives of this group are the kininogens. There are three different kininogens in mammals: H- (high molecular mass, INTERPRO) and L- (low molecular mass) kininogen which are found in a number of species, and T-kininogen that is found only in rat.
- Unclassified cystatins. These are cystatin-like proteins found in a range of organisms: plant phytocystatins, fetuin in mammals, insect cystatins and a puff adder venom cystatin which inhibits metalloproteases of the MEROPS peptidase family M12 (astacin/adamalysin). Also a number of the cystatins-like proteins have been shown to be devoid of inhibitory activity.
All true cystatins inhibit cysteine peptidases of the papain family (MEROPS peptidase family C1), and some also inhibit legumain family enzymes (MEROPS peptidase family C13). These peptidases play key roles in physiological processes, such as intracellular protein degradation (cathepsins B, H and L), are pivotal in the remodelling of bone (cathepsin K), and may be important in the control of antigen presentation (cathepsin S, mammalian legumain). Moreover, the activities of such peptidases are increased in pathophysiological conditions, such as cancer metastasis and inflammation. Additionally, such peptidases are essential for several pathogenic parasites and bacteria. Thus in animals cystatins not only have capacity to regulate normal body processes and perhaps cause disease when down-regulated, but in other organisms may also participate in defence against biotic and abiotic stress.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||cysteine-type endopeptidase inhibitor activity (GO:0004869)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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This superfamily includes cystatins and cathelicidins . The cystatin superfamily comprises cysteine protease inhibitors that play key regulatory roles in protein degradation processes. The progenitor of this superfamily was most probably intracellular and lacked a signal peptide and disulfide bridges, much like the extant Giardia cystatin. A primordial gene duplication produced two ancestral eukaryotic lineages, cystatins and stefins. Stefins - included in Pfam:PF00031 - remain encoded by a single or a small number of genes throughout the eukaryotes, whereas the cystatins have undergone a more complex and dynamic evolution through numerous gene and domain duplications .
The clan contains the following 4 members:Cathelicidins Cystatin PP1 Spp-24
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
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We make a range of alignments for each Pfam-A family:
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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Curation and family details
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|Author:||Bateman A, Sonnhammer ELL|
|Number in seed:||43|
|Number in full:||2054|
|Average length of the domain:||88.60 aa|
|Average identity of full alignment:||17 %|
|Average coverage of the sequence by the domain:||54.95 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||16|
|Download:||download the raw HMM for this family|
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How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Cystatin domain has been found. There are 81 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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