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Science 336 (6085): 1168-1171

Copyright © 2012 by the American Association for the Advancement of Science

The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol

Paul J. Barrett,1,* Yuanli Song,1,* Wade D. Van Horn,1 Eric J. Hustedt,2 Johanna M. Schafer,1 Arina Hadziselimovic,1 Andrew J. Beel,1 Charles R. Sanders1,{dagger}

Abstract: C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by {gamma}-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 {gamma}-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.

1 Department of Biochemistry, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
2 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: chuck.sanders{at}vanderbilt.edu


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