Structural Change in β-Sheet A of Z α1-Antitrypsin Is Responsible for Accelerated Polymerization and Disease

The presence of the Z mutation (Glu342Lys) is responsible for more than 95% of α1-antitrypsin (α1AT) deficiency cases. It leads to increased polymerization of the serpin α1AT during its synthesis and in circulation. It has been proposed that the Z mutation results in a conformational change within the folded state of antitrypsin that enhances its polymerization. In order to localize the conformational change, we have created two single tryptophan mutants of Z α1AT and analyzed their fluorescence properties. α1AT contains two tryptophan residues that are located in distinct regions of the molecule: Trp194 at the top of β-sheet A and Trp238 on β-sheet B. We have replaced each tryptophan residue individually with a phenylalanine in order to study the local environment of the remaining tryptophan residue in both M and Z α1AT. A detailed fluorescence spectroscopic analysis of each mutant was carried out, and we detected differences in the emission spectrum, the Stern–Volmer constant for potassium iodide quenching and the anisotropy of only Trp194 in Z α1AT compared to M α1AT. Our data reveal that the Z mutation results in a conformational change at the top of β-sheet A but does not affect the structural integrity of β-sheet B.

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► Z antitrypsin has the same stability as wild-type antitrypsin but polymerizes faster.
► Our studies show that Z antitrypsin is in a nonnative conformation.
► Z antitrypsin's altered conformation promotes polymerization.