The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.
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.
Department of Biochemistry, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
Paul J
PJ
Barrett
Yuanli
Y
Song
Wade D
WD
Van Horn
Eric J
EJ
Hustedt
Johanna M
JM
Schafer
Arina
A
Hadziselimovic
Andrew J
AJ
Beel
Charles R
CR
Sanders
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002784:Cholesterol / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008823:Micelles; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D016564:Amyloid beta-Protein Precursor; D008823:Micelles; D010446:Peptide Fragments; C543304:amyloid beta-protein precursor C-terminal fragment beta, human; D002784:Cholesterol