title: Evidence from solid-state NMR for nonhelical conformations in the transmembrane domain of the amyloid precursor protein.
abstract: The amyloid precursor protein (APP) is subject to proteolytic processing by γ-secretase within neuronal membranes, leading to Alzheimer's disease-associated β-amyloid peptide production by cleavage near the midpoint of the single transmembrane (TM) segment of APP. Conformational properties of the TM segment may affect its susceptibility to γ-secretase cleavage, but these properties have not been established definitively, especially in bilayer membranes with physiologically relevant lipid compositions. In this article, we report an investigation of the APP-TM conformation, using (13)C chemical shifts obtained with two-dimensional solid-state NMR spectroscopy as site-specific conformational probes. We find that the APP-TM conformation is not a simple α-helix, particularly at 37°C in multilamellar vesicles with compositions that mimic the composition of neuronal cell membranes. Instead, we observe a mixture of helical and nonhelical conformations at the N- and C-termini and in the vicinity of the γ-cleavage site. Conformational plasticity of the TM segment of APP may be an important factor in the γ-secretase cleavage mechanism.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Lu
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Wai-Ming
authors.initials: WM
authors.lastname: Yau
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: robertty@mail.nih.gov.
authors.forename: Robert
authors.initials: R
authors.lastname: Tycko
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D008051:Lipid Bilayers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013696:Temperature
chemical_list: D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; C028694:1-palmitoyl-2-oleoylphosphatidylcholine