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Structure of iron regulatory protein-RNA complex solved

The surprising structure and properties of a protein responsible for regulating the transport, storage and use of iron -- as it binds its target RNA -- are described by researchers from the University of Illinois at Chicago in the Dec. 22 issue of Science.

Iron is an essential nutrient, and defects in uptake and metabolism that result in either deficiencies or overload of iron cause a variety of diseases and disorders, including heart disease, arthritis and cancer.

The iron regulating protein, called IRP1, has two structural forms, each with important functions within the cell.

When serving as one of two regulators of cellular iron metabolism through its control of gene expression, the tightly coiled IRP1 opens up to expose sites that bind messenger RNA at sites on the RNA called iron responsive elements, or IREs, that are common in genes involved in iron metabolism.

In its alternate form, IRP1 binds a cluster of iron and sulfur atoms to act as an important metabolic enzyme called aconitase. The assembly and disassembly of the iron/sulfur cluster in the aconitase form appears to be an effective mechanism for regulating IRP1 activity.

"We found that when IRP1 releases the iron/sulfur cluster and opens up to bind RNA, it undergoes an extraordinary, unexpected rearrangement," said William Walden, professor of microbiology and immunology at UIC and lead author of the study.

"This is the crucial step in understanding the specialized cellular processes that have evolved to maintain internal iron concentrations at the appropriate safe and useful levels and is important to the future design of therapeutic targets," Walden said.

IRP1 is a very large protein, composed of about 900 amino acids arranged into four major domains.

"We expected that IRP1 would open up the two major domains facing each other along a hinge, rather like a clam shell, to accommodate the RNA binding," Walden said. "What
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Contact: Jeanne Galatzer-Levy
jgala@uic.edu
312-996-1583
University of Illinois at Chicago
21-Dec-2006


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