Reference : Reduced global copperativity is a common feature underlying the amyloidogenicity of p...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/16640
Reduced global copperativity is a common feature underlying the amyloidogenicity of pathogenic lysozyme mutations
English
Dumoulin, Mireille mailto [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 mailto [Université de Liège - ULg > 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 > > >]
25-Feb-2005
Journal of Molecular Biology
Academic Press Ltd Elsevier Science Ltd
346
3
773-788
Yes (verified by ORBi)
International
0022-2836
London
[en] human lysozyme ; amyloidogenic variants ; camel antibody fragments ; hydrogen/deuterium exchange ; stabilization
[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.
http://hdl.handle.net/2268/16640

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Open access
DumoulinJMB2005.pdfNo commentaryPublisher postprint897.4 kBView/Open

Bookmark and Share SFX Query

All documents in ORBi are protected by a user license.