title: Structural heterogeneity in transmembrane amyloid precursor protein homodimer is a consequence of environmental selection.
abstract: The 99 amino acid C-terminal fragment of amyloid precursor protein (C99), consisting of a single transmembrane (TM) helix, is known to form homodimers. Homodimers can be processed by γ-secretase to produce amyloid-β (Aβ) protein, which is implicated in Alzheimer's disease (AD). While knowledge of the structure of C99 homodimers is of great importance, experimental NMR studies and simulations have produced varying structural models, including right-handed and left-handed coiled-coils. In order to investigate the structure of this critical protein complex, simulations of the C99(15-55) homodimer in POPC membrane bilayer and DPC surfactant micelle environments were performed using a multiscale approach that blends atomistic and coarse-grained models. The C99(15-55) homodimer adopts a dominant right-handed coiled-coil topology consisting of three characteristic structural states in a bilayer, only one of which is dominant in the micelle. Our structural study, which provides a self-consistent framework for understanding a number of experiments, shows that the energy landscape of the C99 homodimer supports a variety of slowly interconverting structural states. The relative importance of any given state can be modulated through environmental selection realized by altering the membrane or micelle characteristics.
authors.affiliation: Department of Chemistry, Boston University , Boston, Massachusetts 02215, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Dominguez
authors.forename: Leigh
authors.initials: L
authors.lastname: Foster
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Meredith
authors.forename: John E
authors.initials: JE
authors.lastname: Straub
authors.forename: D
authors.initials: D
authors.lastname: Thirumalai
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D008823:Micelles; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D016564:Amyloid beta-Protein Precursor; D008823:Micelles