A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis

作者：Sato Takeshi; Tang Tzu chun; Reubins Gabriella; Fei Jeffrey Z; Fujimoto Taiki; Kienlen Campard Pascal; Constantinescu Stefan N; Octave Jean Noel; Aimoto Saburo; Smith Steven O^*

来源：Proceedings of the National Academy of Sciences, 2009, 106(5): 1421-1426.

DOI：10.1073/pnas.0812261106

• Alzheimer's disease
• GxxxG motifs
• progressive cleavage
• solid-state-NMR spectroscopy

Processing of amyloid precursor protein (APP) by gamma-secretase is the last step in the formation of the A beta 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 A beta 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.

• 出版日期2009-2-3