Local cooperativity in the unfolding of an amyloidogenic variant of human lysozyme.
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.
Canet
Denis
D
Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QH, UK.
Last
Alexander M
AM
Tito
Paula
P
Sunde
Margaret
M
Spencer
Andrew
A
Archer
David B
DB
Redfield
Christina
C
Robinson
Carol V
CV
Dobson
Christopher M
CM
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
D006859:Hydrogen; D009113:Muramidase