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Molecular Mechanism of Z ?1-Antitrypsin Deficiency.

ABSTRACT: The Z mutation (E342K) of ?1-antitrypsin (?1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional ?1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z ?1-AT and why 15% of the expressed Z ?1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in ?1-AT. The results reveal that Z ?1-AT has a labile strand 5 of the central ?-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central ?-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z ?1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central ?-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z ?1-AT deficiency.

SUBMITTER: Huang X

PROVIDER: S-EPMC4957051 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Molecular Mechanism of Z α1-Antitrypsin Deficiency.

Huang Xin X Zheng Ying Y Zhang Fei F Wei Zhenquan Z Wang Yugang Y Carrell Robin W RW Read Randy J RJ Chen Guo-Qiang GQ Zhou Aiwu A

The Journal of biological chemistry 20160531 30

The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z α1-AT and why 15% of the expressed Z α1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the ...[more]

PMID: 27246852

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Project description:α1-antitrypsin (AAT) deficiency is a common autosomal recessive hereditary disorder, with a high risk for the development of early-onset panacinar emphysema. AAT, produced primarily in the liver, functions to protect the lung from neutrophil protease; with AAT deficiency, unimpeded neutrophil proteases destroy the lung parenchyma. AAT is susceptible to oxidative damage resulting in an inability to inhibit its target proteases, neutrophil elastase, and cathepsin G. The major sites of oxidative modification on the AAT molecule are methionine residues 351 and 358. We have previously demonstrated that an engineered variant of AAT that resists oxidation by modifying both protein surface methionines (M351V and M358L) provides antiprotease protection, despite oxidative stress. In mice, intravenous delivery of the modified AAT(AVL) variant by AAV serotype 8, AAV8hAAT(AVL), primarily to the liver resulted in long-term expression of an AAT that resists oxidative inactivation. In this study, we evaluated the safety of intravenous administration of AAV8hAAT(AVL) in a dose-escalating, blinded, placebo-controlled toxicology study in wild-type mice. The study assessed organ histology and clinical pathology findings of mice, intravenously administered AAV8hAAT(AVL) at three doses (5.0 × 1011, 5.0 × 1012, and 5.0 × 1013 genome copies [gc]/kg), compared to control mice injected intravenously with phosphate-buffered saline. As previously demonstrated, administration of AAV8hAAT(AVL) resulted in dose-dependent expression of high, potentially therapeutic, levels of serum human AAT protein that persist for at least 6 months. Antibodies against the AAV8 capsid were elicited as expected, but there was no antibody detected against the AAT(AVL) protein generated by the AAV8hAAT(AVL) vector. There was no morbidity or mortality observed in the study. The data demonstrate that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effect attributed to AAV8hAAT(AVL) vector at any dose. This study demonstrates that AAV8hAAT(AVL) has a safety profile consistent with the requirements for proceeding to a clinical study.

Dataset Information

Molecular Mechanism of Z ?1-Antitrypsin Deficiency.

Publications

Molecular Mechanism of Z α1-Antitrypsin Deficiency.

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