Molecular determinants and thermodynamics of the amyloid precursor protein transmembrane domain implicated in Alzheimer's disease.

ABSTRACT: The deposition of toxic amyloid-β (Aβ) peptide aggregates in the brain is a hallmark of Alzheimer's disease. The intramembrane proteolysis by γ-secretase of the amyloid precursor protein β-carboxy-terminal fragment (APP-βCTF) constitutes the final step in the production of Aβ peptides. Mounting evidence suggests that APP-βCTF is a transmembrane domain (TMD) dimer, and that dimerization might modulate the production of Aβ species that are prone to aggregation and are therefore most toxic. We combined experimental and computational approaches to study the molecular determinants and thermodynamics of APP-βCTF dimerization, and we produced a unifying structural model that reconciles much of the published data. Using a cell assay that exploits a dimerization-dependent activator of transcription

SUBMITTER: Wang H 

PROVIDER: S-EPMC3082318 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature