Serpine

Serpins (acronym for "serine-protease inhibitors") are a unique group of glycoproteins that occur in all living organisms and are characterized by highly conserved, complex protein tertiary structures (these protein tertiary structures can be found in eukaryotes, plants and viruses). Serpins typically consist of 400 amino acids with variable N- and C-terminal chains. Their protein skeleton consists of 9 alpha helices and 3 beta leaflet structures. The oligosaccharides bound in the glycoprotein structure influence the efficiency of the inhibitory effect.

Serpins are unique in that within their molecule, certain highly conserved protein sequences spontaneously organize themselves into a metastable (under tension) tertiary beta leaflet structure. The mechanism by which this particular tertiary structure is formed is still unknown.

The special beta leaflet structure is essential for the inhibition of proteinases. Any proteolytic activity of the inhibitor leads to a change in the tertiary structure and thus to an irreversible loss of its inhibitory property. Errors in the tertiary structure (e.g. through gene polymorphisms) lead to an inactive, latent serpin.

The serpines are divided into 16 classes, which are identified by the names A-P. Within each class there is a consecutive numbering. In the official nomenclature, antithrombin, for example, is given the name SerpinC1.

The following proteins belong to the serpins:

• Antithrombin controls the proteolytic coagulation cascade
• C1-Inhibitor controls complement activation
• Plasminogen activator inhibitor (PAI-1 and PAI-2) controls fibrinolysis. PAI-2 is a serpin expressed by keratinocytes, activated monocytes and placenta. Serum levels of PAI-2 are physiologically very low except during pregnancy (formed by placenta). The expression of PAI-2 is influenced by various factors. The expression of PAI-2 is induced by various growth factors (EGF, M-CSF), hormones (glucocorticoids, vitamin D3) and cytokines (TNF-alpha, IL-1, IL-2). Endotoxins can also stimulate PAL-2 expression.
• Alpha-antitrypsin modulates the reconstruction of connective tissue.
• Other serpins such as angiotensinogen, thyroxine, the corticosteroid binding globulin TBG1 have lost their inhibitory function and take over other biological functions.

Serpinopathies are diseases that are associated with mutations in the corresponding serpin genes. The best known serpinopathy is the C1 esterase inhibitor deficiency or mutations in the gene of plasminogen activator inhibitor 1.

Serpins were originally named as such when they were considered exclusively as inhibitors of serine proteases. This proved to be incorrect, since not all proteins of the Serpin family act as serine protease inhibitors (they can also inhibit other proteases ) and not every serine protease inhibitor is a member of this family. Serpins play an important role in the regulation of many physiological processes. In human blood plasma, the most important protease inhibitors belong to the serpine family. They account for about 10 % of the total protein.

1. Dolmer K et al (2012) How the serpin α1-proteinase inhibitor folds. J Biol Chem 287:12425-12432.
2. Horvath AJ et al (2011) Methods to measure the kinetics of protease inhibition by serpins. Methods Enzyme 501:223-35.
3. Miyata T et al (2005) Serpinopathy and endoplasmic reticulum stress. Med Mol Morphol 38:73-78.
4. Iwaki T et al (2017) Mutation in a highly conserved glycine residue in strand 5B of plasminogen activator inhibitor 1 causes polymerisation. Thromb haemost 117:860-869.