Pathways & interactions
Proteinase inhibitor I25C, fetuin, conserved site (IPR001363)
Short name: Prot_inh_fetuin_CS
The cystatins are a superfamily of similar proteins present in mammals, birds, fish, insects, plants and protozoa. In general they are potent peptidase inhibitors [PMID: 3555466, PMID: 2107324, PMID: 1855589, PMID: 14587292] belonging to MEROPS inhibitor family I25, clan IH.The type 1 cystatins or stefins (A and B) are mainly intracellular, the type 2 cystatins (C, D, E/M, F, G, S, SN and SA) are extracellular, and the type 3 cystatins (L- and H-kininogens) are intravascular proteins. 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.
This family of proteinase inhibitors are cystatins belonging to MEROPS inhibitor family I25 (clan IH), subfamily I25C. They are primarily metalloprotease inhibitors, which include snake venom anti-hemorrhagic factors and the mammalian fetuins, for example:
- Anti-hemorrhagic factor BJ46a, which is a potent inhibitor of atrolysin and jararhagin (MEROPS peptidase family M12) from the venomous snake Bothrops jararaca [PMID: 11358523].
- Anti-hemorrhagic factor, HSF, from the Japanese Habu snake (Trimeresurus flavoviridis). HSF contains two N-terminal cystatin domains which show a remarkable sequence homology (about 50%) to those of plasma glycoproteins such as alpha 2-HS (human) and fetuin (bovine) and to a lesser extent to that of HRG (human). In spite of the presence of cystatin domains, HSF does not inhibit cysteine proteinases such as papain and cathepsin B but does inhibit several metalloproteases in Habu venom [PMID: 1478916].
- Mammalian fetuins have been demonstrated to bind to matrix metalloproteinase (MMPs, MEROPS peptidase family M10). This binding protects the MMPs from autolytic degradation without interfering with their enzymatic activity [PMID: 14644044].
Fetuins are known to consist of three domains: two tandemly arranged N-terminal cystatin domains (D1 and D2) and an unrelated domain (D3) located in the C-terminal region [PMID: 1372866, PMID: 1373325]. When compared with the other members of this family, D3, especially its N-terminal half, varies greatly due to deletions, insertions or substitutions. Sequence comparisons suggest that the conformation of the human alpha2HS glycoprotein differs greatly from that of other members of this family. Human fetuin is a heterodimer of chains A and B, which are derived by cleavage of a connecting peptide from a common precursor. It is synthesised in the liver and selectively concentrated in bone matrix. It has a wide functional diversity having been shown to be involved in immune response, bone formation and resorption.
Mammalian fetuin also called alpha-2-HS-glycoprotein, bone sialic acid-containing protein (BSP), countertrypin or PP63, is expressed in a tissue- and development-specific pattern, which seems to be significantly different between species [PMID: 1707273, PMID: 9133634].
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GO:0005615 extracellular space