title: A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.
abstract: Processing of amyloid precursor protein (APP) by gamma-secretase is the last step in the formation of the Abeta peptides associated Alzheimer's disease. Solid-state NMR spectroscopy is used to establish the structural features of the transmembrane (TM) and juxtamembrane (JM) domains of APP that facilitate proteolysis. Using peptides corresponding to the APP TM and JM regions (residues 618-660), we show that the TM domain forms an alpha-helical homodimer mediated by consecutive GxxxG motifs. We find that the APP TM helix is disrupted at the intracellular membrane boundary near the epsilon-cleavage site. This helix-to-coil transition is required for gamma-secretase processing; mutations that extend the TM alpha-helix inhibit epsilon cleavage, leading to a low production of Abeta peptides and an accumulation of the alpha- and beta-C-terminal fragments. Our data support a progressive cleavage mechanism for APP proteolysis that depends on the helix-to-coil transition at the TM-JM boundary and unraveling of the TM alpha-helix.
authors.affiliation: Department of Biochemistry and Cell Biology, Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794-5115, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.forename: Tzu-Chun
authors.initials: TC
authors.lastname: Tang
authors.forename: Gabriella
authors.initials: G
authors.lastname: Reubins
authors.forename: Jeffrey Z
authors.initials: JZ
authors.lastname: Fei
authors.forename: Taiki
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Octave
authors.forename: Saburo
authors.initials: S
authors.lastname: Aimoto
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000737:chemistry; D019281:Dimerization; D006868:Hydrolysis; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins