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J. Biol. Chem., Vol. 277, Issue 45, 42579-42587, November 8, 2002
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From the Children's Hospital Oakland Research Institute, The
Research Institute of the Children's Hospital and Medical Center
Oakland, 5700 Martin Luther King, Jr. Way, Oakland, California
94609-1673
Synthesis of proteins for iron homeostasis is
regulated by specific, combinatorial mRNA/protein interactions
between RNA stem-loop structures (iron-responsive elements, IREs) and
iron-regulatory proteins (IRP1 and IRP2), controlling either mRNA
translation or stability. The transferrin receptor 3'-untranslated
region (TfR-3'-UTR) mRNA is unique in having five IREs, linked by
AU-rich elements. A C-bulge in the stem of each TfR-IRE folds into an IRE that has low IRP2 binding, whereas a loop/bulge in the stem of the
ferritin-IRE allows equivalent IRP1 and IRP2 binding. Effects of
multiple IRE interactions with IRP1 and IRP2 were compared between the
native TfR-3'-UTR sequence (5xIRE) and RNA with only 3 or 2 IREs. We
show 1) equivalent IRP1 and IRP2 binding to multiple TfR-IRE RNAs; 2)
increased IRP-dependent nuclease resistance of 5xIRE
compared with lower IRE copy-number RNAs; 3) distorted TfR-IRE helix
structure within the context of 5xIRE, detected by
Cu-(phen)2 binding/cleavage, that coincides
with ferritin-IRE conformation and enhanced IRP2 binding; and 4)
variable IRP1 and IRP2 expression in human cells and during development
(IRP2-mRNA predominated). Changes in TfR-IRE structure conferred by
the full length TfR-3'-UTR mRNA explain in part evolutionary
conservation of multiple IRE-RNA, which allows TfR mRNA
stabilization and receptor synthesis when IRP activity varies, and
ensures iron uptake for cell growth.
Multiple, Conserved Iron-responsive Elements in the
3'-Untranslated Region of Transferrin Receptor mRNA Enhance
Binding of Iron Regulatory Protein 2*
*
This work was supported in part by National Institutes of
Health Grant DK-20251.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Children's Hospital
Oakland Research Institute, 5700 Martin Luther King, Jr. Way, Oakland, CA 94609-1672. Tel.: 510-450-7670; Fax: 510-597-7131; E-mail: etheil@chori.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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