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Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM
N. Ripin, J. Boudet, MM. Duszczyk, A. Hinniger, M. Faller, M. Krepl, A. Gadi, RJ. Schneider, J. Šponer, NC. Meisner-Kober, FH. Allain,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1915 to 6 months ago
Freely Accessible Science Journals
from 1915 to 6 months ago
PubMed Central
from 1915 to 6 months ago
Europe PubMed Central
from 1915 to 6 months ago
Open Access Digital Library
from 1915-01-01
Open Access Digital Library
from 1915-01-15
- MeSH
- 3' Untranslated Regions MeSH
- Dimerization MeSH
- ELAV Proteins chemistry MeSH
- ELAV-Like Protein 1 chemistry genetics MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- RNA Recognition Motif genetics MeSH
- Tumor Suppressor Proteins chemistry MeSH
- RNA-Binding Proteins chemistry genetics MeSH
- Ribonucleoside Diphosphate Reductase chemistry MeSH
- AU Rich Elements genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Human antigen R (HuR) is a key regulator of cellular mRNAs containing adenylate/uridylate-rich elements (AU-rich elements; AREs). These are a major class of cis elements within 3' untranslated regions, targeting these mRNAs for rapid degradation. HuR contains three RNA recognition motifs (RRMs): a tandem RRM1 and 2, followed by a flexible linker and a C-terminal RRM3. While RRM1 and 2 are structurally characterized, little is known about RRM3. Here we present a 1.9-Å-resolution crystal structure of RRM3 bound to different ARE motifs. This structure together with biophysical methods and cell-culture assays revealed the mechanism of RRM3 ARE recognition and dimerization. While multiple RNA motifs can be bound, recognition of the canonical AUUUA pentameric motif is possible by binding to two registers. Additionally, RRM3 forms homodimers to increase its RNA binding affinity. Finally, although HuR stabilizes ARE-containing RNAs, we found that RRM3 counteracts this effect, as shown in a cell-based ARE reporter assay and by qPCR with native HuR mRNA targets containing multiple AUUUA motifs, possibly by competing with RRM12.
Department of Microbiology New York University School of Medicine New York NY 10016
Novartis Institutes for BioMedical Research 4002 Basel Switzerland
References provided by Crossref.org
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- $a Ripin, Nina $u Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland; nina.ripin@mol.biol.ethz.ch nicole.meisner-kober@sbg.ac.at frederic.allain@mol.biol.ethz.ch. Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
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- $a Human antigen R (HuR) is a key regulator of cellular mRNAs containing adenylate/uridylate-rich elements (AU-rich elements; AREs). These are a major class of cis elements within 3' untranslated regions, targeting these mRNAs for rapid degradation. HuR contains three RNA recognition motifs (RRMs): a tandem RRM1 and 2, followed by a flexible linker and a C-terminal RRM3. While RRM1 and 2 are structurally characterized, little is known about RRM3. Here we present a 1.9-Å-resolution crystal structure of RRM3 bound to different ARE motifs. This structure together with biophysical methods and cell-culture assays revealed the mechanism of RRM3 ARE recognition and dimerization. While multiple RNA motifs can be bound, recognition of the canonical AUUUA pentameric motif is possible by binding to two registers. Additionally, RRM3 forms homodimers to increase its RNA binding affinity. Finally, although HuR stabilizes ARE-containing RNAs, we found that RRM3 counteracts this effect, as shown in a cell-based ARE reporter assay and by qPCR with native HuR mRNA targets containing multiple AUUUA motifs, possibly by competing with RRM12.
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