Unknown

Dataset Information

0

The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.

ABSTRACT: C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by ?-secretase to release the amyloid-? polypeptides, which are associated with Alzheimer's disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved ? helix, making it well suited for processive cleavage by ?-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer's therapeutics.

SUBMITTER: Barrett PJ 

PROVIDER: S-EPMC3528355 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.

Barrett Paul J PJ   Song Yuanli Y   Van Horn Wade D WD   Hustedt Eric J EJ   Schafer Johanna M JM   Hadziselimovic Arina A   Beel Andrew J AJ   Sanders Charles R CR  

Science (New York, N.Y.) 20120601 6085

C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release the amyloid-β polypeptides, which are associated with Alzheimer's disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved α helix, making it well suited f  ...[more]

Similar Datasets

Unknown Verteporfin is a substrate-selective γ-secretase inhibitor that binds the amyloid precursor protein transmembrane domain.
| S-EPMC8968665 | biostudies-literature
Unknown Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein.
| S-EPMC10230161 | biostudies-literature
Unknown Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its ?-Helical Conformation, and Inhibits ?-Secretase Nonselectively in Liposomes.
| S-EPMC6051911 | biostudies-literature
Unknown Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor?
| S-EPMC2572687 | biostudies-literature
Unknown Structural Characterization of the Amyloid Precursor Protein Transmembrane Domain and Its γ-Cleavage Site.
| S-EPMC6645296 | biostudies-literature
Unknown Molecular determinants and thermodynamics of the amyloid precursor protein transmembrane domain implicated in Alzheimer's disease.
| S-EPMC3082318 | biostudies-literature
Unknown Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein.
| S-EPMC3758481 | biostudies-literature
Unknown Substrate sequence influences ?-secretase modulator activity, role of the transmembrane domain of the amyloid precursor protein.
| S-EPMC3220583 | biostudies-literature
Unknown Evidence from solid-state NMR for nonhelical conformations in the transmembrane domain of the amyloid precursor protein.
| S-EPMC3030151 | biostudies-literature
Unknown The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10.
| S-EPMC9127328 | biostudies-literature