%0 Journal Article
%A Lammich, Sven
%A Kamp, Frits
%A Wagner, Judith
%A Nuscher, Brigitte
%A Zilow, Sonja
%A Ludwig, Ann-Katrin
%A Willem, Michael
%A Haass, Christian
%T Translational repression of the disintegrin and metalloprotease ADAM10 by a stable G-quadruplex secondary structure in its 5'-untranslated region.
%J The journal of biological chemistry
%V 286
%N 52
%@ 0021-9258
%C Bethesda, Md.
%I Soc.60645
%M DZNE-2020-02717
%P 45063-45072
%D 2011
%X Anti-amyloidogenic processing of the amyloid precursor protein APP by α-secretase prevents formation of the amyloid-β peptide, which accumulates in senile plaques of Alzheimer disease patients. α-Secretase belongs to the family of a disintegrin and metalloproteases (ADAMs), and ADAM10 is the primary candidate for this anti-amyloidogenic activity. We recently demonstrated that ADAM10 translation is repressed by its 5'-UTR and that in particular the first half of ADAM10 5'-UTR is responsible for translational repression. Here, we asked whether specific sequence motifs exist in the ADAM10 5'-UTR that are able to form complex secondary structures and thus potentially inhibit ADAM10 translation. Using circular dichroism spectroscopy, we demonstrate that a G-rich region between nucleotides 66 and 94 of the ADAM10 5'-UTR forms a highly stable, intramolecular, parallel G-quadruplex secondary structure under physiological conditions. Mutation of guanines in this sequence abrogates the formation of the G-quadruplex structure. Although the G-quadruplex structure efficiently inhibits translation of a luciferase reporter in in vitro translation assays and in living cells, inhibition of G-quadruplex formation fails to do so. Moreover, expression of ADAM10 was similarly repressed by the G-quadruplex. Mutation of the G-quadruplex motif results in a significant increase of ADAM10 levels and consequently APPsα secretion. Thus, we identified a critical RNA secondary structure within the 5'-UTR, which contributes to the translational repression of ADAM10.
%K 5' Untranslated Regions: physiology
%K ADAM Proteins: biosynthesis
%K ADAM Proteins: genetics
%K ADAM10 Protein
%K Amyloid Precursor Protein Secretases: biosynthesis
%K Amyloid Precursor Protein Secretases: genetics
%K HEK293 Cells
%K Humans
%K Membrane Proteins: biosynthesis
%K Membrane Proteins: genetics
%K Mutation
%K Nucleic Acid Conformation
%K Protein Biosynthesis: physiology
%K 5' Untranslated Regions (NLM Chemicals)
%K Membrane Proteins (NLM Chemicals)
%K Amyloid Precursor Protein Secretases (NLM Chemicals)
%K ADAM Proteins (NLM Chemicals)
%K ADAM10 Protein (NLM Chemicals)
%K ADAM10 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:22065584
%2 pmc:PMC3248004
%R 10.1074/jbc.M111.296921
%U https://pub.dzne.de/record/136395