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- Title
Local cooperativity in the unfolding of an amyloidogenic variant of human lysozyme.
- Authors
Canet, Denis; Last, Alexander M; Tito, Paula; Sunde, Margaret; Spencer, Andrew; Archer, David B; Redfield, Christina; Robinson, Carol V; Dobson, Christopher M
- Abstract
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.
- Publication
Nature structural biology, 2002, Vol 9, Issue 4, p308
- ISSN
1072-8368
- Publication type
Journal Article
- DOI
10.1038/nsb768