title: 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, 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 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-βCTF 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 γ-secretase and to lead to a variation in Aβ levels.
authors: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors: Hao
authors: H
authors: Wang
authors: Laura
authors: L
authors: Barreyro
authors: Davide
authors: D
authors: Provasi
authors: Imane
authors: I
authors: Djemil
authors: Celia
authors: C
authors: Torres-Arancivia
authors: Marta
authors: M
authors: Filizola
authors: Iban
authors: I
authors: Ubarretxena-Belandia
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D013816:Thermodynamics
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases