Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM
| Autor: | Nina Ripin, Julien Boudet, Malgorzata M. Duszczyk, Alexandra Hinniger, Michael Faller, Miroslav Krepl, Abhilash Gadi, Robert J. Schneider, Jiří Šponer, Nicole C. Meisner-Kober, Frédéric H.-T. Allain |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Magnetic Resonance Spectroscopy
Ribonucleoside Diphosphate Reductase RNA-binding protein Crystallography X-Ray ELAV-Like Protein 1 03 medical and health sciences 0302 clinical medicine NMR spectroscopy Humans multiple register 3' Untranslated Regions 030304 developmental biology AU Rich Elements 0303 health sciences Multidisciplinary Tumor Suppressor Proteins Crystal structure RNA-Binding Proteins Biological Sciences Biophysics and Computational Biology ELAV Proteins PNAS Plus Dimerization RNA Recognition Motif 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 116 (8) |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.3929/ethz-b-000328390 |
| Popis: | 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. Proceedings of the National Academy of Sciences of the United States of America, 116 (8) ISSN:0027-8424 ISSN:1091-6490 |
| Databáze: | OpenAIRE |
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