Mutations Which Impede Loop/Sheet Polymerization Enhance the Secretion of Human α1-Antitrypsin Deficiency Variants

α1-Antitrypsin plasma deficiency variants which form hepatic inclusion bodies within the endoplasmic pathway include the common Z variant (Glu342→ Lys) and the rarer α1-antitrypsin Siiyama(Ser53→ Phe). It has been proposed that retention of both abnormal proteins is accompanied by a common mechanism of loop-sheet polymerization with the insertion of the reactive center loop of one molecule into a β-pleated sheet of another. We have compared the biosynthesis, glycosylation, and secretion of normal, Z and Siiyamavariants of α1-antitrypsin using Xenopus oocytes. Siiyamaand Z α1-antitrypsin both duplicated the secretory defect seen in hepatocytes that results in decreased plasma α1-antitrypsin levels. Digestion with endoglycosidase H localized both variants to a pre-Golgi compartment. The mutation Phe51→ Leu abolished completely the intracellular blockage of Siiyamaα1-antitrypsin and reduced significantly the retention of Z α1-antitrypsin. The secretory properties of M and Z α1-antitrypsin variants containing amino acid substitutions designed to decrease loop mobility and sheet insertion were investigated. A reduction in intracellular levels of Z α1-antitrypsin was achieved with the replacement of P11/12alanines by valines. Thus a decrease in Z and Siiyamaα1-antitrypsin retention was observed with mutations which either closed the A sheet or decreased loop mobility at the loop hinge region.