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

Science, 1 June 2012
Vol. 336, Issue 6085, p. 1168-1171
DOI: 10.1126/science.1219988

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

  1. Paul J. Barrett1,*,
  2. Yuanli Song1,*,
  3. Wade D. Van Horn1,
  4. Eric J. Hustedt2,
  5. Johanna M. Schafer1,
  6. Arina Hadziselimovic1,
  7. Andrew J. Beel1,
  8. Charles R. Sanders1,
  1. 1Department of Biochemistry, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
  2. 2Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
  1. To whom correspondence should be addressed. E-mail: chuck.sanders{at}vanderbilt.edu
  1. * These authors contributed equally to this work.

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.

  • Received for publication 2 February 2012.
  • Accepted for publication 13 April 2012.

Citation:

P. J. Barrett, Y. Song, W. D. Van Horn, E. J. Hustedt, J. M. Schafer, A. Hadziselimovic, A. J. Beel, and C. R. Sanders, The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol. Science 336, 1168-1171 (2012).

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