GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42

Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
The EMBO Journal (Impact Factor: 10.43). 04/2007; 26(6):1702-12. DOI: 10.1038/sj.emboj.7601616
Source: PubMed


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.

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    • "cell–celladhesion (Soba et al., 2005) and its proteolytic processing (Munter et al., 2007). Dimerization sites have been reported to be located at the positively charged loop encompassing cysteines 98 and 105 of the E1 domain (Dahms et al., 2010; Kaden et al., 2008), within the E2 domain (Lee et al., 2011; Wang and Ha, 2004; Xue et al., 2011) and within the transmembrane segment of APP (Munter et al., 2007; Nadezhdin et al., 2012). In addition, dimerization was reported to require the interaction of the entire ectodomain with long heparin sulfates (Gralle et al., 2006). "
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