Protease inhibition by serpins controls an array of biological processes, including coagulation and inflammation, and consequently these proteins are the target of medical research. Their unique conformational change also makes them of interest to the structural biology and protein folding research communities. The conformational-change mechanism confers certain advantages, but it also has drawbacks: serpins are vulnerable to mutations that can result in serpinopathies such as protein misfolding and the formation of inactive long-chain polymers. Serpin polymerisation not only reduces the amount of active inhibitor, but also leads to accumulation of the polymers, causing cell death and organ failure.
Although most serpins control proteolytic cascades, some proteins with a serpin structure are not enzyme inhibitors, but instead perform diverse functions such as storage (as in egg white—ovalbumin), transport as in hormone carriage proteins (thyroxine-binding globulin, cortisol-binding globulin) and molecular chaperoning (HSP47). The term serpin is used to describe these members as well, despite their non-inhibitory function, since they are evolutionarily related.
Protease inhibitory activity in blood plasma was first reported in the late 1800s, but it was not until the 1950s that the serpins antithrombin and alpha 1-antitrypsin were isolated. Initial research focused on their role in human disease: Alpha 1-antitrypsin deficiency is one of the most common genetic disorders, causing emphysema, and antithrombin deficiency results in thrombosis.
In the 1980s it became clear that these inhibitors were part of superfamily of related proteins that included both protease inhibitors (e.g. Alpha 1-antitrypsin) and non-inhibitory members (e.g. ovalbumin). The name "Serpin" was coined based on the most common activity of the superfamily (serine protease inhibitors). Around the same time, the first structures were solved for serpin proteins (first in the relaxed, and later in the stressed conformation). The structures indicated that the inhibitory mechanism involved an unusual conformational change and prompted the subsequent structural focus of serpin studies.
Over 1000 serpins have now been identified, including 36 human proteins, as well as molecules in all kingdoms of life—animals, plants, fungi, bacteria, and archaea—and some viruses. In the 2000s, a systematic nomenclature was introduced in order to categorise members of the serpin superfamily based on their evolutionary relationships. Serpins are therefore the largest and most diverse superfamily of protease inhibitors.
Most serpins are protease inhibitors, targeting extracellular, chymotrypsin-like serine proteases. These proteases possess a nucleophilic serine residue in a catalytic triad in their active site. Examples include thrombin, trypsin, and human neutrophil elastase. Serpins act as irreversible, suicide inhibitors by trapping an intermediate of the protease's catalytic mechanism.
Some serpins inhibit other protease classes, typically cysteine proteases, and are termed "cross-class inhibitors". These enzymes differ from serineproteases in that they use a nucleophilic cysteine residue, rather than a serine, in their active site. Nonetheless, the enzymatic chemistry is similar, and the mechanism of inhibition by serpins is the same for both classes of protease.