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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

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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]

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