The Z mutation of α1-antitrypsin is at residue P17 (17 residues proximal to the P1 reactive center) at the head of strand 5 of β-sheet A and the base of the mobile reactive loop. The mutation opens β-sheet A, thereby favoring the insertion of the reactive loop of a second α1-antitrypsin molecule to form a dimer (Figure 2). This process can then extend to form polymers that tangle in the endoplasmic reticulum of the liver and form inclusion bodies (5). Support for this model comes from the demonstration that purified Z α1-antitrypsin forms chains of polymers when incubated under physiological conditions (3). The rate can be accelerated by raising the temperature to 41 C and can be blocked by introducing peptides that compete with the loop for annealing to β-sheet A. The role of polymerization in vivo has been confirmed by the finding of α1-antitrypsin polymers in inclusion bodies from the liver of a Z α1-antitrypsin homozygote with cirrhosis (3) and in cell lines expressing the Z variant (6). Moreover, point mutations that block polymerization increased the secretion of mutants of α1-antitrypsin from a Xenopus oocyte expression system (7). We have now defined the following pathway by which α1-antitrypsin and other members of the serpin superfamily form polymers (equation 1 from ref. 8):