Folding of A+U-rich RNA elements modulates AUF1 binding: Potential roles in regulation of mRNA turnover

Gerald M. Wilson, Kristina Sutphen, Keng Yu Chuang, Gary Brewer

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

In mammals, A+U-rich elements (AREs) are potent cis-acting determinants of rapid cytoplasmic mRNA turnover. Recognition of these sequences by AUF1 is associated with acceleration of mRNA decay, likely involving recruitment or assembly of multi-subunit transacting complexes. Previously, we demonstrated that AUF1 deletion mutants formed tetramers on U-rich RNA substrates by sequential addition of protein dimers (Wilson, G. M., Sun, Y., Lu, H., and Brewer, G. (1999) J. Biol. Chem. 274, 33374-33381). Here, we show that binding of the full-length p37 isoform of AUF1 to these RNAs proceeds via a similar mechanism, allowing delineation of equilibrium binding constants for both stages of tetramer assembly. However, association of AUF1 with the ARE from tumor necrosis factor (TNFα) mRNA was significantly inhibited by magnesium ions. Further fluorescence and hydrodynamic experiments indicated that Mg2+ induced or stabilized a conformational change in the TNFα ARE. Based on the solution of parameters describing both the protein-RNA and Mg2+-RNA equilibria, we present a dynamic, global equilibrium binding model describing the relationship between Mg2+ and AUF1 binding to the TNFα ARE. These studies provide the first evidence that some AREs may adopt higher order RNA structures that regulate their interaction with trans-acting factors and indicate that mRNA structural remodeling has the potential to modulate the turnover rates of some ARE-containing mRNAs.

Original languageEnglish (US)
Pages (from-to)8695-8704
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number12
DOIs
StatePublished - Mar 23 2001

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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