Structural change in β-sheet A of Z α(1)-antitrypsin is responsible for accelerated polymerization and disease.

The presence of the Z mutation (Glu342Lys) is responsible for more than 95% of α(1)-antitrypsin (α(1)AT) deficiency cases. It leads to increased polymerization of the serpin α(1)AT 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 α(1)AT and analyzed their fluorescence properties. α(1)AT 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 α(1)AT. 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 α(1)AT compared to M α(1)AT. 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.