Serine protease inhibitor
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Serine protease inhibitors or serpins (short for serine protease inhibitor) are a group of proteins that inhibit peptidases (old name: proteases). Although initially considered a class of protease inhibitors (agents that block the action of protein-degrading enzymes), it was discovered later that it has members that do not inhibit any enzymes, but serve as storage proteins (ovalbumin, in egg white), carriage proteins (thyroxine-binding globulin, steroid-binding globulin) and hormone precursors (angiotensinogen). The term serpin is used for these members as well, despite their noninhibitory function.
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Form and function
Serine proteases are defined by the presence of a serine residue in their active domain. The inhibitory serpins have in common that they inhibit this group of enzymes. They are part of the larger group of protease inhibitors.
Although the function of serpins varies widely, they share a number of structural details: all have three beta sheets and eight or nine alpha helixes in a typical configuration. Mutations in these areas may lead to dysfunction and disease ("serpinopathy").
Specificity
Many serpins are specific for particular proteases (most of them serine proteases), but they can show nonspecific inhibition of other serine proteases as well (e.g. thrombin). Additionally, pathological forms can occasionally inhibit the wrong serine protease.
Members
Proteins in the serpin class:
- Alpha 1-antitrypsin (the most important serpin, often simply referred to as protease inhibitor);
- Alpha 1-antichymotrypsin;
- Alpha 2-antiplasmin (inhibitor of fibrinolysis);
- Antithrombin (inhibitor of coagulation);
- Complement 1-inhibitor;
- Neuroserpin (recently discovered, mutated in some familial forms of dementia);
- Plasminogen activator inhibitor-1 and 2 (fibrinolysis);
- Protein Z-related protease inhibitor (ZPI, inactivates factor Xa and factor XIa)
Classification
In 2001, a consensus (Silverman et al) was published in which the circa 500 serpins were classified in sixteen clades (based on structural similarity), with the remaining ten as orphans. Gettins (2002) cites evidence that related human serpins may have arisen due to gene duplication, as many are clustered on particular chromosomes.
References
- Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E, Salvesen GS, Travis J, Whisstock JC. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 2001;276:33293-6. PMID 11435447.
- Gettins PGW. Serpin structure, mechanism and function. Chem Rev 2002;102:4751-803. DOI 10.1021/cr010170+ (http://dx.doi.org/10.1021/cr010170+).
External links
- PDB molecule of the month: Serine protease inhibitor (http://nist.rcsb.org/pdb/molecules/pdb53_1.html)