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

Paul J. Barrett, Yuanli Song, Wade D. Van Horn, Eric J. Hustedt, Johanna M. Schafer, Arina Hadziselimovic, Andrew J. Beel, Charles R. Sanders

Research output: Contribution to journalArticlepeer-review

297 Scopus citations

Abstract

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 for processive cleavage by γ-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.

Original languageEnglish (US)
Pages (from-to)1168-1171
Number of pages4
JournalScience
Volume336
Issue number6085
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • General

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