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J. Biol. Chem., Vol. 283, Issue 2, 1094-1103, January 11, 2008

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Eukaryotic Initiation Factor (eIF) 1 Carries Two Distinct eIF5-binding Faces Important for Multifactor Assembly and AUG Selection^*

Mikhail Reibarkh¹, Yasufumi Yamamoto¹, Chingakham Ranjit Singh¹, Federico del Rio, Amr Fahmy, Bumjun Lee, Rafael E. Luna, Miki Ii, Gerhard Wagner², and Katsura Asano³

From the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 and the Molecular, Cellular, and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, Kansas 66506

Eukaryotic initiation factor (eIF) 1 is a small protein (12 kDa) governing fidelity in translation initiation. It is recruited to the 40 S subunit in a multifactor complex with Met-, eIF2, eIF3, and eIF5 and binds near the P-site. eIF1 release in response to start codon recognition is an important signal to produce an 80 S initiation complex. Although the ribosome-binding face of eIF1 was identified, interfaces to other preinitiation complex components and their relevance to eIF1 function have not been determined. Exploiting the solution structure of yeast eIF1, here we locate the binding site for eIF5 in its N-terminal tail and at a basic/hydrophobic surface area termed KH, distinct from the ribosome-binding face. Genetic and biochemical studies indicate that the eIF1 N-terminal tail plays a stimulatory role in cooperative multifactor assembly. A mutation altering the basic part of eIF1-KH is lethal and shows a dominant phenotype indicating relaxed start codon selection. Cheung et al. recently demonstrated that the alteration of hydrophobic residues of eIF1 disrupts a critical link to the preinitiation complex that suppresses eIF1 release before start codon selection ( Cheung, Y.-N., Maag, D., Mitchell, S. F., Fekete, C. A., Algire, M. A., Takacs, J. E., Shirokikh, N., Pestova, T., Lorsch, J. R., and Hinnebusch, A. (2007) Genes Dev. 21, 1217-1230[Abstract/Free Full Text] ). Interestingly, eIF1-KH includes the altered hydrophobic residues. Thus, eIF5 is an excellent candidate for the direct partner of eIF1-KH that mediates the critical link. The direct interaction at eIF1-KH also places eIF5 near the decoding site of the 40 S subunit.

Received for publication, October 2, 2007 , and in revised form, November 1, 2007.

The atomic coordinates and structure factors (code 2OGH) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grants GM64781 (to K. A.) and CA68262 and GM47467 (to G. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: gerhard_wagner{at}hms.harvard.edu.

³ To whom correspondence may be addressed. E-mail: kasano{at}ksu.edu.

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