Vickers, Sarah;
Aldobiyan, Ibrahim;
Lowen, Sarah M;
Irving, James A;
Lomas, David A;
Thalassinos, Konstantinos;
(2025)
Top-Down Ion Mobility Mass Spectrometry Reveals a Disease Associated Conformational Ensemble of Alpha-1-antitrypsin.
Journal of the American Chemical Society
10.1021/jacs.4c18139.
(In press).
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Abstract
Mutants of members of the serpin superfamily can undergo nonamyloid aggregation to form polymeric chains that are associated with disease. This is typified by Z alpha-1-antitrypsin (Glu342Lys) that accumulates as polymers within hepatocytes to cause cirrhosis. We have used ion mobility mass spectrometry and electron-capture dissociation to directly observe and characterize novel intermediates formed during polymerization. Our data are congruent with an ensemble of conformations that are monomeric but maintained in a partially misfolded metastable state in which ∼12% of the molecule at the C-terminus is displaced. The application of these techniques to Z alpha-1-antitrypsin polymers isolated from human liver revealed a molecular species most consistent with a polymer mediated by an intermolecular C-terminal domain insertion. These findings establish a previously unobserved progression of pathogenic structural changes and thereby extend the mechanism of alpha-1-antitrypsin polymerization. They additionally demonstrate the strengths of native top-down ion mobility mass spectrometry in characterizing misfolding intermediates and proteins isolated from human tissue.
| Type: | Article |
|---|---|
| Title: | Top-Down Ion Mobility Mass Spectrometry Reveals a Disease Associated Conformational Ensemble of Alpha-1-antitrypsin |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/jacs.4c18139 |
| Publisher version: | https://doi.org/10.1021/jacs.4c18139 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, ELECTRON-CAPTURE DISSOCIATION, MOLECULAR-BASIS, MECHANISM, SERPIN, POLYMERIZATION, PROTEINS, POLYMERS, INSIGHTS, GLYCOSYLATION, SPECTROSCOPY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10208451 |
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