GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42.
Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases leads to the generation of amyloid-beta (Abeta) peptides with varying lengths. Particularly Abeta42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease (AD). However, the precise molecular mechanism of Abeta42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Abeta species produced. In a neuronal cell system, mutations of glycine residues G29 and G33 of the GxxxG motif gradually attenuate the TMS dimerization strength, specifically reduce the formation of Abeta42, leave the level of Abeta40 unaffected, but increase Abeta38 and shorter Abeta species. We show that glycine residues G29 and G33 are part of a dimerization site within the TMS, but do not impair oligomerization of the APP ectodomain. We conclude that gamma-secretase cleavages of APP are intimately linked to the dimerization strength of the substrate TMS. The results demonstrate that dimerization of APP TMS is a risk factor for AD due to facilitating Abeta42 production.
Munter
Lisa-Marie
LM
Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
Voigt
Philipp
P
Harmeier
Anja
A
Kaden
Daniela
D
Gottschalk
Kay E
KE
Weise
Christoph
C
Pipkorn
Rüdiger
R
Schaefer
Michael
M
Langosch
Dieter
D
Multhaup
Gerd
G
D000544:Alzheimer Disease / Q000235:genetics*; D020816:Amino Acid Motifs / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D015153:Blotting, Western; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases