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81  structures 367  species 2  interactions 2054  sequences 20  architectures

Family: Cystatin (PF00031)

Summary: Cystatin domain

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Cystatin Edit Wikipedia article

Proteinase inhibitor I25, cystatin
Salivary Cystatin from Ornithodoros moubata.png
Crystal structure of an immunomodulatory salivary cystatin from the soft tick Ornithodoros moubata from PDB entry 3L0R.[1]
Identifiers
Symbol Prot_inh_cystat
Pfam PF00031
Pfam clan CL0121
InterPro IPR000010
SMART SM00043
PROSITE PDOC00259

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.[2][3][4] Cystatins mainly inhibit peptidase enzymes (another term for proteases) belonging to peptidase families C1 (papain family) and C13 (legumain family). They are know to mis-fold to form amyloid deposits and are implicated in several diseases.

Types[edit]

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 [5])
  • 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.

Human cystatins[edit]

See also[edit]

References[edit]

  1. ^ ; 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. PMID 20545626. ; rendered with PyMOL
  2. ^ 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. 
  3. ^ Abrahamson M, Alvarez-fernandez M, Nathanson CM (2003). "Cystatins". Biochem. Soc. Symp. (70): 179–199. PMID 14587292. 
  4. ^ 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. 
  5. ^ 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.  edit

Further reading[edit]

  • Lee C, Bongcam-Rudloff E, Sollner C, Jahnen-Dechent W, Claesson-Welsh L (2009). "Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein". Front. Biosci. 14 (14): 2911–22. doi:10.2741/3422. PMID 19273244. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR000010


This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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.

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cystatin (CL0121), which contains the following 4 members:

Cathelicidins Cystatin PP1 Spp-24

Alignments

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. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(43)
Full
(2054)
Representative proteomes NCBI
(2132)
Meta
(5)
RP15
(158)
RP35
(262)
RP55
(454)
RP75
(813)
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Format an alignment

  Seed
(43)
Full
(2054)
Representative proteomes NCBI
(2132)
Meta
(5)
RP15
(158)
RP35
(262)
RP55
(454)
RP75
(813)
Alignment:
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Sequence:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(43)
Full
(2054)
Representative proteomes NCBI
(2132)
Meta
(5)
RP15
(158)
RP35
(262)
RP55
(454)
RP75
(813)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

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Trees

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

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: cystatin;
Type: Domain
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 information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 20.9
Trusted cut-off 20.9 20.9
Noise cut-off 20.8 20.8
Model length: 94
Family (HMM) version: 16
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 2 interactions for this family. More...

Cystatin Peptidase_C1

Structures

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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