High-resolution ex vivo NMR spectroscopy of human Z α1-antitrypsin

Alistair M. Jagger, Christopher A. Waudby, James A. Irving (), John Christodoulou () and David A. Lomas ()
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Alistair M. Jagger: University College London
Christopher A. Waudby: University of London
James A. Irving: University College London
John Christodoulou: University of London
David A. Lomas: University College London

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Genetic mutations predispose the serine protease inhibitor α1-antitrypsin to misfolding and polymerisation within hepatocytes, causing liver disease and chronic obstructive pulmonary disease. This misfolding occurs via a transiently populated intermediate state, but our structural understanding of this process is limited by the instability of recombinant α1-antitrypsin variants in solution. Here we apply NMR spectroscopy to patient-derived samples of α1-antitrypsin at natural isotopic abundance to investigate the consequences of disease-causing mutations, and observe widespread chemical shift perturbations for methyl groups in Z AAT (E342K). By comparison with perturbations induced by binding of a small-molecule inhibitor of misfolding we conclude that they arise from rapid exchange between the native conformation and a well-populated intermediate state. The observation that this intermediate is stabilised by inhibitor binding suggests a paradoxical approach to the targeted treatment of protein misfolding disorders, wherein the stabilisation of disease-associated states provides selectivity while inhibiting further transitions along misfolding pathways.

Date: 2020
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DOI: 10.1038/s41467-020-20147-7

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