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GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42
Author(s) -
Munter LisaMarie,
Voigt Philipp,
Harmeier Anja,
Kaden Daniela,
Gottschalk Kay E,
Weise Christoph,
Pipkorn Rüdiger,
Schaefer Michael,
Langosch Dieter,
Multhaup Gerd
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601616
Subject(s) - biology , transmembrane protein , sequence (biology) , amyloid (mycology) , transmembrane domain , peptide sequence , computational biology , bioinformatics , genetics , evolutionary biology , gene , botany , receptor
Processing of the amyloid precursor protein (APP) by β‐ and γ‐secretases leads to the generation of amyloid‐β (Aβ) peptides with varying lengths. Particularly Aβ42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease (AD). However, the precise molecular mechanism of Aβ42 generation has remained unclear. Here, we show that an amino‐acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Aβ 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 Aβ42, leave the level of Aβ40 unaffected, but increase Aβ38 and shorter Aβ 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 γ‐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 Aβ42 production.