Mar 29, 2011

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

Journal of Molecular Biology
Hao WangI Ubarretxena-Belandia

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, we identified specific dimerization-affecting mutations located mostly at the N-terminus of the TMD of APP-βCTF. The ability of selected mutants to affect the dimerization of full-length APP-βCTF was confirmed by fluorescence resonance energy transfer experiments. Free-energy estimates of the wild type and mutants of the TMD of APP-βCTF derived from enhanced molecular dynamics simulations showed that the dimeric state is composed of differen...Continue Reading

Mentioned in this Paper

Pathologic Cytolysis
Egg White Structure
Thermodynamics
Molecular Dynamics
In Silico
Presenilins
Familial Alzheimer Disease (FAD)
Maleimides
Naphthalenes
Deoxyribonuclease I

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