The Amyloid Precursor Protein Maintains an Ideal&Alpha-Helical Conformation in the Lipid Bilayer

Abstract

The Amyloid Precursor Protein (APP) is a type-I transmembrane glycoprotein present at the neuronal synapse. The proteolytic cleavage by γ-secretase produces amyloid-β (A&β) peptides of different lengths, the deposition of which is an early indicator of Alzheimer's disease (AD). At present, there is no consensus on the conformation of the APP transmembrane (TM) domain at the biological membrane. Although structures have been determined by nuclear magnetic resonance (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 helical conformation once embedded in a membrane bilayer. APP-TM is highly flexible however, and its secondary structure is strongly influenced by the surrounding lipid environment. This behavior is confirmed when analyzing in silico the atomistic APP-TM population observed by residual dipolar couplings and double electron-electron resonance (DEER) spectroscopy. These structural and dynamic features are probably critical in the proteolytic processing of APP by the γ-secretase enzyme, as suggested by mutants mimicking influencing the APP flexibility that shows a relevant increase in the production of A&β38 compared to physiological A&β40 peptides.View Large Image | View Hi-Res Image | Download PowerPoint Slide