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

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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
Issue number6085
StatePublished - Jun 1 2012


ASJC Scopus subject areas

  • General

Cite this

Barrett, P. J., Song, Y., Van Horn, W. D., Hustedt, E. J., Schafer, J. M., Hadziselimovic, A., Beel, A. J., & Sanders, C. R. (2012). The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science, 336(6085), 1168-1171.