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J. Biol. Chem., Vol. 276, Issue 12, 8695-8704, March 23, 2001

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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, and Gary Brewer^§

From the Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

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 trans-acting 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 (TNF) mRNA was significantly inhibited by magnesium ions. Further fluorescence and hydrodynamic experiments indicated that Mg²⁺ induced or stabilized a conformational change in the TNF 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 TNF 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.

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