Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM

Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2935-2944. doi: 10.1073/pnas.1808696116. Epub 2019 Feb 4.


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.

Keywords: NMR spectroscopy; RNA-binding protein; crystal structure; dimerization; multiple register.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • AU Rich Elements / genetics
  • Crystallography, X-Ray
  • Dimerization
  • ELAV Proteins / chemistry*
  • ELAV-Like Protein 1 / chemistry*
  • ELAV-Like Protein 1 / genetics
  • Humans
  • Magnetic Resonance Spectroscopy
  • RNA Recognition Motif / genetics*
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / genetics
  • Ribonucleoside Diphosphate Reductase / chemistry
  • Tumor Suppressor Proteins / chemistry


  • 3' Untranslated Regions
  • ELAV Proteins
  • ELAV-Like Protein 1
  • RNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ribonucleotide reductase M2
  • RRM1 protein, human
  • Ribonucleoside Diphosphate Reductase