Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased Aβ production.
Proteolysis of the β C-terminal fragment (β-CTF) of the amyloid precursor protein generates the Aβ peptides associated with Alzheimer's disease. Familial mutations in the β-CTF, such as the A21G Flemish mutation, can increase Aβ secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the β-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces β sheet structure of C55 from Leu17 to Ala21, an inhibitory region near the site of the mutation, and increases α-helical structure from Gly25 to Gly29, in a region near the membrane surface and thought to interact with cholesterol. Cholesterol also increases Aβ peptide secretion, and we show that the incorporation of cholesterol into model membranes enhances the structural changes induced by the Flemish mutant, suggesting a common link between familial mutations and the cellular environment.
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Tzu-Chun
TC
Tang
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Yi
Y
Hu
Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium.
Pascal
P
Kienlen-Campard
Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium.
Laetitia
L
El Haylani
Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium.
Marie
M
Decock
Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, Brussels 1200, Belgium.
Joanne
J
Van Hees
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Ziao
Z
Fu
Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium.
Jean-Noel
JN
Octave
Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, Brussels 1200, Belgium.
Stefan N
SN
Constantinescu
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA. Electronic address: steven.o.smith@stonybrook.edu.
Steven O
SO
Smith
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003412:Cricetulus; D006801:Humans; D008051:Lipid Bilayers; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D002784:Cholesterol