α1-Antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy

The serine proteinase inhibitors, or serpins, are a superfamily of proteins that are found in a wide range of species, including plants, viruses, and humans.The family includes proteins as diverse as 1 -antichymotrypsin, C1 inhibitor, antithrombin, and plasminogen activator inhibitor-1, which have key regulatory functions in the inflammatory, complement, coagulation, and fibrinolytic cascades.Members of the serpin superfamily are characterized by more than 30% sequence homology with 1 -antitrypsin and conservation of tertiary structure.The structure is based on three -sheets (A-C) and an exposed mobile reactive loop that presents a peptide sequence as a pseudosubstrate for the target proteinase.In the case of 1 -antitrypsin, the loop presents the P1-P1 residues methionine-serine as a "bait" for neutrophil elastase.After docking, the proteinase is inactivated by a mousetrap action that swings it from the upper to the lower pole of the protein in association with the insertion of the reactive loop as an extra strand in -sheet A. This six-stranded protein bound to its target enzyme is then recognized by hepatic receptors and cleared from the circulation.The reactive loop/-sheet A interaction of serpins is crucial for their role as effective antiproteinases but also renders them liable to undergo conformational transitions that cause disease.Point mutations can destabilize -sheet A to allow incorporation of the loop of another serpin molecule (see ref. 1 for review).Sequential reactive loop insertion results in chains of polymers that are retained within the cell of synthesis.This process is best characterized in mutants of 1antitrypsin that result in liver damage, a consequence of protein retention within hepatocytes (see Perlmutter, this Perspective series, ref. 2; and ref. 3).It is also recognized to underlie plasma deficiency of anti-thrombin, C1 inhibitor, and 1 -antichymotrypsin in association with thrombosis, angio-edema, and emphysema, respectively.Moreover, in the neuron-specific proteinase inhibitor neuroserpin, the same process underlies a novel early-onset inclusion body dementia termed familial encephalopathy with neuroserpin inclusion bodies (FENIB).We review here the role of serpin dysfunction and polymerization in a range of diseases that can be grouped together as the serpinopathies.Our understanding of the structural basis of polymerization provides novel strategies to block polymer formation in vitro.The long-term aim must be to turn these into therapies that are effective in preventing polymerization in vivo.