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Title

The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets.

AuthorsScheiba, Rafael M.; Ibáñez de Okapua, Alain; Díaz-Quintana, Antonio; Cruz-Gallardo, Isabel CSIC ORCID; Martínez-Cruz, Luis Alfonso; Martínez-Chantar, María L.; Blanco, Francisco J. CSIC ORCID ; Díaz-Moreno, Irene CSIC ORCID
KeywordsDimerization
Human antigen R (HuR)
Nuclear Magnetic Resonance (NMR)
RNA binding protein (RBP)
RNA binding
RNA recognition motif (RRM)
Serine phosphorylation
Issue DateOct-2014
PublisherTaylor & Francis
CitationRNA Biology, 11(10): 1250-61 (2014)
AbstractHuman antigen R (HuR) is a 32 kDa protein with 3 RNA Recognition Motifs (RRMs), which bind to Adenylate and uridylate Rich Elements (AREs) of mRNAs. Whereas the N-terminal and central domains (RRM1 and RRM2) are essential for AREs recognition, little is known on the C-terminal RRM3 beyond its implication in HuR oligomerization and apoptotic signaling. We have developed a detergent-based strategy to produce soluble RRM3 for structural studies. We have found that it adopts the typical RRM fold, does not interact with the RRM1 and RRM2 modules, and forms dimers in solution. Our NMR measurements, combined with Molecular Dynamics simulations and Analytical Ultracentrifugation experiments, show that the protein dimerizes through a helical region that contains the conserved W261 residue. We found that HuR RRM3 binds to 5'-mer U-rich RNA stretches through the solvent exposed side of its β-sheet, located opposite to the dimerization site. Upon mimicking phosphorylation by the S318D replacement, RRM3 mutant shows less ability to recognize RNA due to an electrostatic repulsion effect with the phosphate groups. Our study brings new insights of HuR RRM3 as a domain involved in protein oligomerization and RNA interaction, both functions regulated by 2 surfaces on opposite sides of the RRM domain
Publisher version (URL)http://dx.doi.org/10.1080/15476286.2014.996069.
URIhttp://hdl.handle.net/10261/109941
DOIhttp://dx.doi.org/10.1080/15476286.2014.996069.
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