Molecular Determinants and Thermodynamics of the Amyloid Precursor Protein Transmembrane Domain Implicated in Alzheimer's Disease

作者：Wang Hao; Barreyro Laura; Provasi Davide; Djemil Imane; Torres Arancivia Celia; Filizola Marta^*; Ubarretxena Belandia Iban

来源：Journal of Molecular Biology, 2011, 408(5): 879-895.

DOI：10.1016/j.jmb.2011.03.028

• molecular dynamics
• TOXCAT
• FRET
• metadynamics
• amyloid-beta peptide

The deposition of toxic amyloid-beta (A beta) peptide aggregates in the brain is a hallmark of Alzheimer's disease. The intramembrane proteolysis by gamma-secretase of the amyloid precursor protein beta-carboxy-terminal fragment (APP-beta CTF) constitutes the final step in the production of A beta peptides. Mounting evidence suggests that APP-beta CTF is a transmembrane domain (TMD) dimer, and that dimerization might modulate the production of A beta 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-beta CTF 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-beta CTF. The ability of selected mutants to affect the dimerization of full-length APP-beta CTF was confirmed by fluorescence resonance energy transfer experiments. Free-energy estimates of the wild type and mutants of the TMD of APP-beta CTF derived from enhanced molecular dynamics simulations showed that the dimeric state is composed of different arrangements, in which either (709)GXXXA(713) or (700)GXXXG(704)GXXXG(708) interaction motifs can engage in symmetric or asymmetric associations. Mutations along the TMD of APP-beta CTF were found to modulate the relative free energy of the dimeric configurations and to differently affect the distribution of interfaces within the dimeric state. This observation might have important biological implications, since dimers with a different arrangement of the transmembrane helices are likely to be recognized differently by gamma-secretase and to lead to a variation in A beta levels.

• 出版日期2011-5-20