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

Abstract

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 α 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 α 1 -antitrypsin and conservation of tertiary structure.The structure is based on three β-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 α 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 β-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/β-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 β-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 α 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 α 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.