Linked Life Data

19908073

Source:http://linkedlifedata.com/resource/pubmed/id/19908073

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-3-26
pubmed:abstractText
Converging lines of evidence suggest that soluble A beta-amyloid oligomers play a pivotal role in the pathogenesis of Alzheimer's disease, and present direct effectors of synaptic and cognitive dysfunction. Three pathological E22-A beta-amyloid point mutants (E22G, E22K, E22Q) and the deletion mutant E22 Delta exhibit an enhanced tendency to form prefibrillar aggregates. The present study assessed the effect of these four mutations using molecular dynamics simulations and subsequent structural and energetic analyses. Our data shows that E22 plays a unique role in wild type A beta, since it has a destabilising effect on the oligomer structure due to electrostatic repulsion between adjacent E22 side chains. Mutations in which E22 is replaced by an uncharged residue result in higher oligomer stability. This effect is also observed to a lesser extent for the E22K mutation and is consistent with its lower pathogenicity compared to other mutants. Interestingly, deletion of E22 does not destroy the amyloid fold but is compensated by local changes in the backbone geometry that allow the preservation of a structurally important salt bridge. The finding that all mutant oligomers investigated exhibit higher internal stability than the wild type offers an explanation for the experimentally observed enhanced oligomer formation and stability.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0948-5023
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1011-20
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Effect of pathogenic mutations on the structure and dynamics of Alzheimer's A beta 42-amyloid oligomers.
pubmed:affiliation
Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't