title: Transmembrane fragment structures of amyloid precursor protein depend on membrane surface curvature.
abstract: The amyloid β (Aβ) peptide associated with Alzheimer's disease results from processing of the amyloid precursor protein (APP) by secretases. Cleavage of APP by β-secretase produces a 99 amino acid C-terminal fragment of APP (C99) consisting of a single transmembrane (TM) helix. Simulations of C99 congeners and structural studies of C99 in surfactant micelles and lipid vesicles have shown that a key peptide structural motif is a prominent "GG kink," centered at two glycines dividing the TM helix. The flexibility of the GG kink is important in the processing of C99 by γ-secretase. We performed multiscale simulations of C99(15-55) in a DPC surfactant micelle and POPC lipid bilayer in order to elucidate the role of membrane surface curvature in modulating the peptide structure. C99(15-55) in a DPC surfactant micelle possesses a "GG kink," in the TM domain near the dynamic hinge located at G37/G38. Such a kink is not observed in C99(15-55) in a POPC lipid bilayer. Intramolecular interaction between the extracellular and TM domains of C99(15-55) is enhanced in the micelle environment, influencing helical stability, TM helix extension, exposure to water, and depth of insertion in the lipophilic region. Our results show that the fluctuations of the structural ensemble of APP are strongly influenced by membrane surface curvature.
authors.affiliation: Department of Chemistry, Boston University , Boston, Massachusetts 02215, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Dominguez
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Meredith
authors.forename: John E
authors.initials: JE
authors.lastname: Straub
authors.forename: David
authors.initials: D
authors.lastname: Thirumalai
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties
chemical_list: D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; C028694:1-palmitoyl-2-oleoylphosphatidylcholine