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J. Biol. Chem., Vol. 280, Issue 3, 1872-1881, January 21, 2005

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Interaction between the NH₂-terminal Domain of eIF4A and the Central Domain of eIF4G Modulates RNA-stimulated ATPase Activity^*

Nadia L. Korneeva, Eric A. First, Clint A. Benoit, and Robert E. Rhoads

From the Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932

The eukaryotic translation factor 4A (eIF4A) is a member of DEA(D/H)-box RNA helicase family, a diverse group of proteins that couples ATP hydrolysis to RNA binding and duplex separation. eIF4A participates in the initiation of translation by unwinding secondary structure in the 5'-untranslated region of mRNAs and facilitating scanning by the 40 S ribosomal subunit for the initiation codon. eIF4A alone has only weak ATPase and helicase activities, but these are stimulated by eIF4G, eIF4B, and eIF4H. eIF4G has two eIF4A-binding sites, one in the central domain (cp_C3) and one in the COOH-terminal domain (cp_C2). In the current work, we demonstrate that these two eIF4G domains have different effects on the RNA-stimulated ATPase activity of eIF4A. cp_C3 stimulates ATP-hydrolytic efficiency by about 40-fold through two mechanisms: lowering K_m^RNA by 10-fold and raising k_cat by 4-fold. cp_C3 also stimulates RNA cross-linking to eIF4A in an ATP-independent manner. Studies with eIF4G and eIF4A variants suggest a model by which cp_C3 alters the conformation of the catalytic site to favor RNA binding. cp_C2 does not stimulate ATPase activity and furthermore increases both K_m^ATP (at saturating RNA concentrations) and K_m^RNA (at subsaturating ATP concentrations). Both cp_C3 and cp_C2 directly interact with the NH₂-terminal domain of eIF4A, which possesses conserved ATP- and oligonucleotide-binding motifs, but not with the COOH-terminal domain.

Received for publication, June 3, 2004 , and in revised form, October 18, 2004.

^* This work was supported by National Institutes of Health Grant GM20818. Mass spectrometry experiments were subsidized by the LSUHSC-S Research Core Facility. The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Dept. of Biochemistry and Molecular Biology, Louisiana state University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. Tel.: 318-675-5161; Fax: 318-675-5180; E-mail: rrhoad{at}lsuhsc.edu.

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