A Helix-to-coil Transition At The ε-cut Site In The Transmembrane Dimer Of The Amyloid Precursor Protein Is Required For Proteolysis

摘要

Processing of amyloid precursor protein (APP) by γ-secretase is the last step in the formation of the Aβ peptides associated Alzheimer's disease. Solid-state NMR spectroscopy is used to establish the structural features of the transmembrane (TM) and juxtamem-brane (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 α-helical ho-modimer mediated by consecutive GxxxG motifs. We find that the APP TM helix is disrupted at the intracellular membrane boundary near the ε-cleavage site. This helix-to-coil transition is required for γ-secretase processing; mutations that extend the TM α-helix inhibit ε cleavage, leading to a low production of Aβ peptides and an accumulation of the α- and β-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 α-helix.