title: The Z mutation alters the global structural dynamics of α1-antitrypsin.
abstract: α1-Antitrypsin (α1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT 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 α1AT compared to the wild type protein, M α1AT, and so it is unclear why Z α1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z α1AT more dynamic than M α1AT 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 α1AT to reveal the molecular basis of Z α1AT 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 β-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z α1AT sampling a polymerogenic structure thereby causing disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Hughes
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Meklemburg
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, United States of America.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Wintrode
mesh_terms: D000595:Amino Acid Sequence; D041961:Deuterium Exchange Measurement; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D063347:Native Polyacrylamide Gel Electrophoresis; D010455:Peptides / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics*
chemical_list: D010455:Peptides; D000515:alpha 1-Antitrypsin