Linked Life Data

15713462

Source:http://linkedlifedata.com/resource/pubmed/id/15713462

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2005-2-16
pubmed:abstractText
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 alpha-helices that form the core of the alpha-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, and the 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2836
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
346
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
773-88
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15713462-Amino Acid Substitution, pubmed-meshheading:15713462-Amyloidosis, Familial, pubmed-meshheading:15713462-Animals, pubmed-meshheading:15713462-Antibodies, pubmed-meshheading:15713462-Camels, pubmed-meshheading:15713462-Enzyme Stability, pubmed-meshheading:15713462-Humans, pubmed-meshheading:15713462-Kinetics, pubmed-meshheading:15713462-Microscopy, Electron, pubmed-meshheading:15713462-Models, Molecular, pubmed-meshheading:15713462-Muramidase, pubmed-meshheading:15713462-Mutation, pubmed-meshheading:15713462-Nuclear Magnetic Resonance, Biomolecular, pubmed-meshheading:15713462-Protein Denaturation, pubmed-meshheading:15713462-Protein Structure, Secondary, pubmed-meshheading:15713462-Protein Structure, Tertiary, pubmed-meshheading:15713462-Recombinant Proteins, pubmed-meshheading:15713462-Spectrometry, Mass, Electrospray Ionization
pubmed:year
2005
pubmed:articleTitle
Reduced global cooperativity is a common feature underlying the amyloidogenicity of pathogenic lysozyme mutations.
pubmed:affiliation
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't