title: Local cooperativity in the unfolding of an amyloidogenic variant of human lysozyme.
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.
authors.affiliation: Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QH, UK.
authors.forename: Denis
authors.initials: D
authors.lastname: Canet
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Last
authors.forename: Paula
authors.initials: P
authors.lastname: Tito
authors.forename: Margaret
authors.initials: M
authors.lastname: Sunde
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.forename: David B
authors.initials: DB
authors.lastname: Archer
authors.forename: Christina
authors.initials: C
authors.lastname: Redfield
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D006859:Hydrogen; D009113:Muramidase