title: Alpha 1-antitrypsin Siiyama (Ser53-->Phe). Further evidence for intracellular loop-sheet polymerization.
abstract: 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.
authors.affiliation: Department of Haematology, University of Cambridge, United Kingdom.
authors.forename: D A
authors.initials: DA
authors.lastname: Lomas
authors.forename: J T
authors.initials: JT
authors.lastname: Finch
authors.forename: K
authors.initials: K
authors.lastname: Seyama
authors.forename: T
authors.initials: T
authors.lastname: Nukiwa
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
mesh_terms: D000328:Adult; D000818:Animals; D002417:Cattle; D002918:Chymotrypsin / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008107:Liver Diseases / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D008958:Models, Molecular; D009154:Mutation; D010649:Phenylalanine / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers; D012694:Serine / Q000737:chemistry* / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D011108:Polymers; D000515:alpha 1-Antitrypsin; D012694:Serine; D010649:Phenylalanine; D002918:Chymotrypsin