Alpha-1 Antitrypsin: The Protein

Alpha-1 antitrypsin (AAT), alternately referred to as alpha-1 proteinase inhibitor or alpha-1 protease inhibitor, is a member of the serine protease inhibitor (serpin) superfamily comprised of alpha-1 antichymotrypsin, C1 inhibitor, antithrombin, neuroserpin, and others (Stoller and Aboussouan, Am J Respir Crit Care Med 185:246–259, 2012; Ekeowa et al., Clin Sci (Lond) 116:837–850, 2009). AAT is considered the major anti-elastase of the lower respiratory tract based on its unsurpassed ability to inhibit the serine protease, neutrophil elastase (Perlmutter and Pierce, Am J Physiol 257:L147–62, 1989; Gadek et al., J Clin Investig 68:889–898, 1981). In addition to its antiprotease activity, AAT has likewise been shown to have other biological effects, including the ability to modulate both inflammation and apoptosis (Petrache et al., Am J Pathol 169:1155–1166, 2006; Janciauskiene et al., Respir Med 105:1129–1139, 2011). Mutant forms of AAT play a well-documented role in disease pathogenesis: misfolding of AAT protein, accumulation of misfolded protein polymers, and an associated decrease in secreted, functional monomers are known to cause clinical dysfunction and disease through both gain-of-function and loss-of-function mechanisms and are collectively known as “AAT deficiency.” In this section, we review the protein’s history, structural composition, regulation, and functional characteristics.