Perturbations of the straight transmembrane α-helical structure of the amyloid precursor protein affect its processing by γ-secretase.
The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by γ-secretase of its C-terminal fragment produces amyloid-β (Aβ) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly different. Here we show by using molecular simulations that the APP-TM region systematically prefers a straight α-helical conformation once embedded in a membrane bilayer. However, APP-TM is highly flexible, and its secondary structure is strongly influenced by the surrounding lipid environment, as when enclosed in detergent micelles. This behavior is confirmed when analyzing in silico the atomistic APP-TM population observed by residual dipolar couplings and double electron-electron resonance spectroscopy. These structural and dynamic features are critical in the proteolytic processing of APP by the γ-secretase enzyme, as suggested by a series of Gly(700) mutants. Affecting the hydration and flexibility of APP-TM, these mutants invariantly show an increase in the production of Aβ38 compared with Aβ40 peptides, which is reminiscent of the effect of γ-secretase modulators inhibitors.
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Thomas
T
Lemmin
Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Mitko
M
Dimitrov
Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Patrick C
PC
Fraering
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. Electronic address: matteo.dalperaro@epfl.ch.
Matteo
M
Dal Peraro
D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics; D002462:Cell Membrane / Q000737:chemistry*; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry; D017433:Protein Structure, Secondary; D059748:Proteolysis
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases
Amyloid; Amyloid Precursor Protein; Mass Spectrometry (MS); Molecular Dynamics; Secretases; double electron-electron resonance (DEER); electron paramagnetic resonance (EPR) spectroscopy; metadynamics