The Z mutation alters the global structural dynamics of alpha(1)-Antitrypsin

alpha1-Antitrypsin (alpha1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90 of all clinical cases of alpha1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and in vitro. The Glu342Lys mutation removes a salt bridge and a hydrogen bond but does not effect the thermodynamic stability of Z alpha1AT compared to the wild type protein, M alpha1AT, and so it is unclear why Z alpha1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z alpha1AT more dynamic than M alpha1AT and that this change renders the protein more polymerization prone. We have used hydrogen/deuterium exchange combined with mass spectrometry (HXMS) to determine the structural and dynamic differences between native Z and M alpha1AT to reveal the molecular basis of Z alpha1AT polymerization. Our HXMS data shows that the Z mutation significantly perturbs the region around the site of mutation. Strikingly the Z mutation also alters the dynamics of regions distant to the mutation such as the B, D and I helices and specific regions of each beta-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z alpha1AT sampling a polymerogenic structure thereby causing disease