Article (Scientific journals)
Reduced global copperativity is a common feature underlying the amyloidogenicity of pathogenic lysozyme mutations
Dumoulin, Mireille; Canet, Denis; Last, Alexander M. et al.
2005In Journal of Molecular Biology, 346 (3), p. 773-788
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Keywords :
human lysozyme; amyloidogenic variants; camel antibody fragments; hydrogen/deuterium exchange; stabilization
Abstract :
[en] One of the 20 or so human amyloid diseases is associated with the deposition in vital organs of full-length mutational variants of the antibacterial protein lysozyme. Here, we report experimental data that permit a detailed comparison to be made of the behaviour of two of these amyloidogenic variants, I56T and D67H, under identical conditions. Hydrogen/deuterium exchange experiments monitored by NMR and mass spectrometry reveal that, despite their different locations and the different effects of the two mutations on the structure of the native state of lysozyme, both mutations cause a cooperative destabilisation of a remarkably similar segment of the structure, comprising in both cases the beta-domain and the adjacent C-helix. As a result, both variant proteins populate transiently a closely similar, partially unstructured intermediate in which the beta-domain and the adjacent C-helix are substantially and simultaneously unfolded, whereas the three remaining a-helices that form the core of the a-domain still have their native-like structure. We show, in addition, that the binding of a camel antibody fragment, cAb-HuL6, which was raised against wild-type lysozyme, restores to both variant proteins the stability and cooperativity characteristic of the wild-type protein; as a consequence, it inhibits the formation of amyloid fibrils by both variants. These results indicate that the reduction in global cooperativity, an associated ability to populate transiently a specific, partly unfolded intermediate state under physiologically relevant conditions, is a common feature underlying the behaviour of these two pathogenic mutations. The formation of intermolecular interactions between lysozyme molecules that are in this partially unfolded state is therefore likely to be the fundamental trigger of the aggregation process that ultimately leads to the formation and deposition in tissue of amyloid fibrils. (C) 2004 Elsevier Ltd. All rights reserved.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Dumoulin, Mireille  ;  University of Cambridge > Department of Chemistry
Canet, Denis;  University of Oxford > Chemistry Research Laboratory > Oxford Centre for Molecular Sciences
Last, Alexander M.;  University of Oxford > Chemistry Research Laboratory > Oxford Centre for Molecular Sciences
Pardon, Els;  Vrije Universiteit Brussel > Vlaams Interuniversitair Instituut voor Biotechnologie > Department of Molecular and Cellular InteractionsLaboratorium voor Ultrastructuur
Archer, David B.;  University of Nottingham > School of Biology
Muyldermans, Serge;  Vrije Universiteit Brussel > Vlaams Interuniversitair Instituut voor Biotechnologie > Department of Molecular and Cellular InteractionsLaboratorium voor Ultrastructuur
Wyns, Lode;  Vrije Universiteit Brussel > Vlaams Interuniversitair Instituut voor Biotechnologie > Department of Molecular and Cellular InteractionsLaboratorium voor Ultrastructuur
Matagne, André  ;  Université de Liège - ULiège > Département des sciences de la vie > Laboratoire d'Enzymologie et Repliement des Protéines, Centre d'Ingénierie des Protéines
Robinson, Carol V.;  University of Cambridge > Department of Chemistry
Redfield, Christina;  University of Oxford > Chemistry Research Laboratory > Oxford Centre for Molecular Sciences
Dobson, Christopher M.;  University of Cambridge > Department of Chemistry
Language :
English
Title :
Reduced global copperativity is a common feature underlying the amyloidogenicity of pathogenic lysozyme mutations
Publication date :
25 February 2005
Journal title :
Journal of Molecular Biology
ISSN :
0022-2836
eISSN :
1089-8638
Publisher :
Academic Press Ltd Elsevier Science Ltd, London, United Kingdom
Volume :
346
Issue :
3
Pages :
773-788
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 11 July 2009

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