TY  - JOUR
AU  - Lammich, Sven
AU  - Kamp, Frits
AU  - Wagner, Judith
AU  - Nuscher, Brigitte
AU  - Zilow, Sonja
AU  - Ludwig, Ann-Katrin
AU  - Willem, Michael
AU  - Haass, Christian
TI  - Translational repression of the disintegrin and metalloprotease ADAM10 by a stable G-quadruplex secondary structure in its 5'-untranslated region.
JO  - The journal of biological chemistry
VL  - 286
IS  - 52
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.60645
M1  - DZNE-2020-02717
SP  - 45063-45072
PY  - 2011
AB  - 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.
KW  - 5' Untranslated Regions: physiology
KW  - ADAM Proteins: biosynthesis
KW  - ADAM Proteins: genetics
KW  - ADAM10 Protein
KW  - Amyloid Precursor Protein Secretases: biosynthesis
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - HEK293 Cells
KW  - Humans
KW  - Membrane Proteins: biosynthesis
KW  - Membrane Proteins: genetics
KW  - Mutation
KW  - Nucleic Acid Conformation
KW  - Protein Biosynthesis: physiology
KW  - 5' Untranslated Regions (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - ADAM Proteins (NLM Chemicals)
KW  - ADAM10 Protein (NLM Chemicals)
KW  - ADAM10 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22065584
C2  - pmc:PMC3248004
DO  - DOI:10.1074/jbc.M111.296921
UR  - https://pub.dzne.de/record/136395
ER  -