Translational Repression of the Disintegrin and Metalloprotease ADAM10 by a Stable G-quadruplex Secondary Structure in Its 5′-Untranslated Region

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...

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Veröffentlicht in:The Journal of biological chemistry 2011-12, Vol.286 (52), p.45063-45072
Hauptverfasser: Lammich, Sven, Kamp, Frits, Wagner, Judith, Nuscher, Brigitte, Zilow, Sonja, Ludwig, Ann-Katrin, Willem, Michael, Haass, Christian
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Sprache:eng
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Zusammenfassung: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. Translation of the α-secretase ADAM10 is repressed by its 5′-untranslated region (5′-UTR). A G-rich region in the ADAM10 5′-UTR forms a highly stable G-quadruplex secondary structure, which inhibits translation of a luciferase reporter and ADAM10. The G-quadruplex secondary structure is one inhibitory element for ADAM10 translation. Our findings provide new insights in the translational regulation of ADAM10.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.296921