Alpha 1-antitrypsin Siiyama (Ser53-->Phe). Further evidence for intracellular loop-sheet polymerization

• Published in: The Journal of biological chemistry 1993-07, Vol.268 (21), p.15333-15335
• Main Authors: Lomas, D A, Finch, J T, Seyama, K, Nukiwa, T, Carrell, R W
• Format: Article
• Language: English
• Subjects: Adult; alpha 1-Antitrypsin - chemistry; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; alpha 1-Antitrypsin - ultrastructure; Animals; Cattle; Chymotrypsin - metabolism; Homozygote; Humans; Liver Diseases - genetics; Male; Microscopy, Electron; Models, Molecular; Mutation; Phenylalanine - chemistry; Phenylalanine - metabolism; Polymers; Serine - chemistry; Serine - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)82258-X

Antitrypsin Siiyama is a rare example of the deficiency variants of antitrypsin that accumulate in the endoplasmic reticulum of the hepatocyte. The common example is Z antitrypsin, which has a mutation (Glu342-->Lys) at the junction of the head of the fifth strand of the A sheet and the base of the reactive center loop. It was previously shown that Z antitrypsin spontaneously polymerizes due to the insertion of the reactive center loop of one molecule into the A sheet of a second. The mutation in antitrypsin Siiyama (Ser53-->Phe) affects a residue that provides a ridge for the sliding movement that opens the A sheet, and it had been predicted that this would result in the same type of loop-sheet polymerization observed with the Z variant. We confirm this here and show that virtually all the plasma antitrypsin in a homozygote for the Siiyama variant was polymerized due to non-covalent bonding with a loss of accessibility of the reactive center loop. The common basis of the polymerization of Z and Siiyama antitrypsin is supported by identical findings on electron microscopy. Taken together these results confirm that loop-sheet polymerization is a general mechanism and as such is likely to be responsible for the intracellular inclusions associated with liver pathology.