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Hydrogen exchange experiments monitored by NMR and mass spectrometry reveal that the amyloidogenic D67H mutation in human lysozyme significantly reduces the stability of the beta-domain and the adjacent C-helix in the native structure. In addition, mass spectrometric data reveal that transient unfolding of these regions occurs with a high degree of cooperativity. This behavior results in the occasional population of a partially structured intermediate in which the three alpha-helices that form the core of the alpha-domain still have native-like structure, whereas the beta-domain and C-helix are simultaneously substantially unfolded. This finding suggests that the extensive intermolecular interactions that will be possible in such a species are likely to initiate the aggregation events that ultimately lead to the formation of the well-defined fibrillar structures observed in the tissues of patients carrying this mutation in the lysozyme gene.

Original publication




Journal article


Nat Struct Biol

Publication Date





308 - 315


Genetic Variation, Humans, Hydrogen, Hydrogen-Ion Concentration, Kinetics, Magnetic Resonance Spectroscopy, Mass Spectrometry, Models, Molecular, Muramidase, Mutation, Missense, Protein Denaturation, Protein Folding, Protein Structure, Tertiary