Serpins : form, function and dysfunction

Abstract

The serpin superfamily of serine protease inhibitors is one of the most ubiquitous and successful classes of inhibitors in the living world. Their unique mechanism of suicide inhibition has led to much research and several important discoveries. They function via rapid incorporation of a reactive centre loop (RCL) within a β-sheet following the former's proteolysis by the target protease: the serpin thus achieves a conformation which is more stable than the native form. Through this conformational change, the target protease structure is distorted and its function disrupted. Alpha-1-antitrypsin (AAT) has often been studied as an archetype for the serpin superfamily, and is discussed in more detail in this review. Of particular interest are the mutant variants of AAT, which have a tendency to polymerise, and thus offer insights into some mechanisms of serpin polymerisation.