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

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.

SUBMITTER: Jagger AM

PROVIDER: S-EPMC7732992 | biostudies-literature |

REPOSITORIES: biostudies-literature

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