Evidence from solid-state NMR for nonhelical conformations in the transmembrane domain of the amyloid precursor protein.

ABSTRACT: The amyloid precursor protein (APP) is subject to proteolytic processing by ?-secretase within neuronal membranes, leading to Alzheimer's disease-associated ?-amyloid peptide production by cleavage near the midpoint of the single transmembrane (TM) segment of APP. Conformational properties of the TM segment may affect its susceptibility to ?-secretase cleavage, but these properties have not been established definitively, especially in bilayer membranes with physiologically relevant lipid compositions. In this article, we report an investigation of the APP-TM conformation, using (13)C chemical shifts obtained with two-dimensional solid-state NMR spectroscopy as site-specific conformational probes. We find that the APP-TM conformation is not a simple ?-helix, particularly at 37°C in multilamellar vesicles with compositions that mimic the composition of neuronal cell membranes. Instead, we observe a mixture of helical and nonhelical conformations at the N- and C-termini and in the vicinity of the ?-cleavage site. Conformational plasticity of the TM segment of APP may be an important factor in the ?-secretase cleavage mechanism.

SUBMITTER: Lu JX 

PROVIDER: S-EPMC3030151 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature