Journal Article

DZNE-2020-02717

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Translational repression of the disintegrin and metalloprotease ADAM10 by a stable G-quadruplex secondary structure in its 5'-untranslated region.

Lammich, S. (Corresponding author) ; Kamp, F. ; Wagner, J. ; Nuscher, B. ; Zilow, S. ; Ludwig, A.-K. ; Willem, M. ; Haass, C. (Last author)DZNE*

2011
Soc.60645 Bethesda, Md.

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Please use a persistent id in citations: doi:10.1074/jbc.M111.296921

Abstract: 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.

Keyword(s): 5' Untranslated Regions: physiology (MeSH) ; ADAM Proteins: biosynthesis (MeSH) ; ADAM Proteins: genetics (MeSH) ; ADAM10 Protein (MeSH) ; Amyloid Precursor Protein Secretases: biosynthesis (MeSH) ; Amyloid Precursor Protein Secretases: genetics (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Membrane Proteins: biosynthesis (MeSH) ; Membrane Proteins: genetics (MeSH) ; Mutation (MeSH) ; Nucleic Acid Conformation (MeSH) ; Protein Biosynthesis: physiology (MeSH) ; 5' Untranslated Regions ; Membrane Proteins ; Amyloid Precursor Protein Secretases ; ADAM Proteins ; ADAM10 Protein ; ADAM10 protein, human

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Contributing Institute(s):

1. ALS, FTLD and Zebrafish models (AG Haass old)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2011

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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