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| Subject Categories: Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 1702–1712, doi:10.1038/sj.emboj.7601616 Published online 1 March 2007 |
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GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of A 42 |
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| Lisa-Marie Munter1, Philipp Voigt2, Anja Harmeier1, Daniela Kaden1, Kay E Gottschalk3, Christoph Weise1, Rüdiger Pipkorn4, Michael Schaefer2, Dieter Langosch5 and Gerd Multhaup1 |
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1 Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany 2 Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany 3 Chair for Applied Physics, Biophysics and Molecular Materials, Ludwig-Maximilians Universität München, München, Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Lehrstuhl Chemie der Biopolymere, Technische Universität München, Freising, Germany To whom correspondence should be addressed Gerd Multhaup, Institut für Chemie und Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany. Tel.: +49 30 838 55533; Fax: +49 30 838 56509; E-mail: multhaup@chemie.fu-berlin.de Received 2 August 2006; Accepted 29 January 2007; Published online 1 March 2007. |
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| Abstract |
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Processing of the amyloid precursor protein (APP) by - and  -secretases leads to the generation of amyloid- (A) peptides with varying lengths. Particularly A42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease (AD). However, the precise molecular mechanism of A42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the A 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 A42, leave the level of A40 unaffected, but increase A38 and shorter A 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 -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 A42 production. |
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| Keywords: amyloid A, amyloid precursor protein (APP), dimerization, GxxxG, secretase |
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