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Abstract
alpha 1-Antitrypsin plasma deficiency variants which form hepatic inclusion bodies within the endoplasmic pathway include the common Z variant (Glu342-->Lys) and the rarer alpha 1-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 beta-pleated sheet of another. We have compared the biosynthesis, glycosylation, and secretion of normal, Z and Siiyama variants of alpha 1-antitrypsin using Xenopus oocytes. Siiyama and Z alpha 1-antitrypsin both duplicated the secretory defect seen in hepatocytes that results in decreased plasma alpha 1-antitrypsin levels. Digestion with endoglycosidase H localized both variants to a pre-Golgi compartment. The mutation Phe51-->Leu abolished completely the intracellular blockage of Siiyama alpha 1-antitrypsin and reduced significantly the retention of Z alpha 1-antitrypsin. The secretory properties of M and Z alpha 1-antitrypsin variants containing amino acid substitutions designed to decrease loop mobility and sheet insertion were investigated. A reduction in intracellular levels of Z alpha 1-antitrypsin was achieved with the replacement of P11/12 alanines by valines. Thus a decrease in Z and Siiyama alpha 1-antitrypsin retention was observed with mutations which either closed the A sheet or decreased loop mobility at the loop hinge region.
Highlights
IntroductionThe Wessex Medical Trust, and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges
Council, the Wessex Medical Trust, and the Wellcome Trust
A 1-antitrypsin Suyama was shown to have the same association with plasma deficiency and the identical histological finding of hepatic inclusions of mutant inhibitor [3, 7]
Summary
The Wessex Medical Trust, and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. Junction of strand 5 of the six-membered sheet A of the molecule [6] with the base of the mobile loop This alteration in the hinge region is thought to interfere with normal refolding of the reactive center into the A sheet, favoring intermolecular loop insertion with the sequential formation ofloop-sheet polymers [5]. An inhibition ofloop folding would be expected to favor polymerization, but if this is so, the mechanism would be that of A sheet rather than C sheet polymerization We test this possibility here using constructs of M and Z antitrypsin containing replacements in the hinge region designed to constrain loop mobility but which should not effect the mechanism of A sheet opening. The secretory properties of these M and Z chimeric mutants provide evidence as to the mechanism underlying the intracellular polymerization of Z antitrypsin
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