Format

Send to

Choose Destination
J Biol Chem. 2014 Mar 7;289(10):6763-74. doi: 10.1074/jbc.M113.470781. Epub 2014 Jan 27.

Perturbations of the straight transmembrane α-helical structure of the amyloid precursor protein affect its processing by γ-secretase.

Author information

1
From the Institute of Bioengineering and.

Abstract

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.

KEYWORDS:

Amyloid; Amyloid Precursor Protein; Mass Spectrometry (MS); Molecular Dynamics; Secretases; double electron-electron resonance (DEER); electron paramagnetic resonance (EPR) spectroscopy; metadynamics

PMID:
24469457
PMCID:
PMC3945338
DOI:
10.1074/jbc.M113.470781
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center