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J. Biol. Chem., Vol. 279, Issue 11, 10584-10592, March 12, 2004

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Structure of the Catalytic Fragment of Translation Initiation Factor 2B and Identification of a Critically Important Catalytic Residue^*

Thomas Boesen¶, Sarah S. Mohammad||**, Graham D. Pavitt||**, and Gregers R. Andersen¶

From the Department of Molecular Biology, Aarhus University, DK8000 Århus C, Denmark and the ^||Biomolecular Sciences, University of Manchester, Institute of Science and Technology, Manchester, M60 1QD, United Kingdom

Eukaryotic initiation factor (eIF) 2B catalyzes the nucleotide activation of eIF2 to its active GTP-bound state. The exchange activity has been mapped to the C terminus of the eIF2B subunit. We have determined the crystal structure of residues 544-704 from yeast eIF2B at 2.3-Å resolution, and this fragment is an all-helical protein built around the conserved aromatic acidic (AA) boxes also found in eIF4G and eIF5. The eight helices are organized in a manner similar to HEAT repeats. The molecule is highly asymmetric with respect to surface charge and conservation. One area in the N terminus is proposed to be directly involved in catalysis. In agreement with this hypothesis, mutation of glutamate 569 is shown to be lethal. An acidic belt and a second area in the C terminus containing residues from the AA boxes are important for binding to eIF2. Two mutations causing the fatal human genetic disease leukoencephalopathy with vanishing white matter are buried and appear to disrupt the structural integrity of the catalytic domain rather than interfering directly with catalysis or binding of eIF2.

Received for publication, October 8, 2003

The atomic coordinates and structure factors (code 1PAQ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/)..

^* 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 supplementary Table 1.

Both authors contributed equally to this work.

^¶ Supported by the Danish Science Research Council, the Lundbeck Foundation, and National Institutes of Health Grant GM62789-02.

^** Supported by grants from the Biotechnological and Biological Sciences Research Council and the Wellcome Trust (to G. D. P).

To whom correspondence should be addressed: Dept. of Molecular Biology, Aarhus University, Gustav Wieds Vej 10C, DK8000 Århus C, Denmark. Tel.: 45-8942-5024; Fax: 45-8612-3178; E-mail: grand{at}imsb.au.dk.

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