Keeping the Serpin Machine Running Smoothly

Serpins are a widely distributed family of structurally very closely related medium molecular weight proteins (mostly 40–50 kDa) that are primarily known as inhibitors of serine proteinases (hence the origin of the name serpin;Gettins et al. 1996). They are found in most organisms, with notable exceptions being bacteria and fungi. There are both extracellular and intracellular serpins. The proteinase targets are often involved in complex physiological processes that must be carefully regulated both temporally and spatially, such as blood coagulation, fibrinolysis, and inflammation. Some of the best known human serpins are antithrombin, the principal inhibitor of the blood clotting cascade proteinases thrombin and factor Xa, α₁-antitrypsin, the principal inhibitor of elastase secreted by neutrophils at sites of inflammation, and plasminogen activator inhibitor-1 (PAI-1), an inhibitor of the plasminogen activators t-PA and u-PA. Because serpins do not inhibit proteinases by a simple noncovalent lock and key mechanism but, instead, use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties, understanding the common elements of serpin structure, folding and conformational change is at the heart of understanding how serpins function in both normal and pathological states. In this issue, Irving and colleagues report serpin sequence comparisons that provide insight not only into the evolutionary relationships between serpins but also into those residues that must play critical roles for serpin structure and function (Irving et al. 2000).