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Molecular and Cellular Biology, January 1999, p. 807-816, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Ribosomal Pausing and Scanning Arrest as Mechanisms of Translational Regulation from Cap-Distal Iron-Responsive Elements

Efrosyni Paraskeva,dagger Nicola K. Gray,* Britta Schläger, Kristina Wehr, and Matthias W. Hentze

European Molecular Biology Laboratory, D-69117 Heidelberg, Germany

Received 4 June 1998/Returned for modification 23 September 1998/Accepted 8 October 1998

Iron regulatory protein 1 (IRP-1) binding to an iron-responsive element (IRE) located close to the cap structure of mRNAs represses translation by precluding the recruitment of the small ribosomal subunit to these mRNAs. This mechanism is position dependent; reporter mRNAs bearing IREs located further downstream exhibit diminished translational control in transfected mammalian cells. To investigate the underlying mechanism, we have recapitulated this position effect in a rabbit reticulocyte cell-free translation system. We show that the recruitment of the 43S preinitiation complex to the mRNA is unaffected when IRP-1 is bound to a cap-distal IRE. Following 43S complex recruitment, the translation initiation apparatus appears to stall, before linearly progressing to the initiation codon. The slow passive dissociation rate of IRP-1 from the cap-distal IRE suggests that the mammalian translation apparatus plays an active role in overcoming the cap-distal IRE-IRP-1 complex. In contrast, cap-distal IRE-IRP-1 complexes efficiently repress translation in wheat germ and yeast translation extracts. Since inhibition occurs subsequent to 43S complex recruitment, an efficient arrest of productive scanning may represent a second mechanism by which RNA-protein interactions within the 5' untranslated region of an mRNA can regulate translation. In contrast to initiating ribosomes, elongating ribosomes from mammal, plant, and yeast cells are unaffected by IRE-IRP-1 complexes positioned within the open reading frame. These data shed light on a characteristic aspect of the IRE-IRP regulatory system and uncover properties of the initiation and elongation translation apparatus of eukaryotic cells.

* Corresponding author. Present address: Department of Biochemistry, 433 Babcock Dr., University of Wisconsin---Madison, Madison, WI 53706. Phone: (608) 262-0347. Fax: (608) 265-9898. E-mail: ngray{at}biochem.wisc.edu.

dagger Present address: ZMBH, 69120 Heidelberg, Germany.

Molecular and Cellular Biology, January 1999, p. 807-816, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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