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Molecular and Cellular Biology, April 2005, p. 3063-3075, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3063-3075.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

PKR and GCN2 Kinases and Guanine Nucleotide Exchange Factor Eukaryotic Translation Initiation Factor 2B (eIF2B) Recognize Overlapping Surfaces on eIF2

Madhusudan Dey,^1, Bruce Trieselmann,^1,, Emily G. Locke,¹ Jingfang Lu,¹ Chune Cao,¹ Arvin C. Dar,² Thanuja Krishnamoorthy,¹ Jinsheng Dong,¹ Frank Sicheri,² and Thomas E. Dever^1*

Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland,¹ Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada²

Received 8 December 2004/ Returned for modification 10 January 2005/ Accepted 17 January 2005

Four stress-responsive protein kinases, including GCN2 and PKR, phosphorylate eukaryotic translation initiation factor 2 (eIF2) on Ser51 to regulate general and gene-specific protein synthesis. Phosphorylated eIF2 is an inhibitor of its guanine nucleotide exchange factor, eIF2B. Mutations that block translational regulation were isolated throughout the N-terminal OB-fold domain in Saccharomyces cerevisiae eIF2, including those at residues flanking Ser51 and around 20 Å away in the conserved motif K₇₉GYID₈₃. Any mutation at Glu49 or Asp83 blocked translational regulation; however, only a subset of these mutations impaired Ser51 phosphorylation. Substitution of Ala for Asp83 eliminated phosphorylation by GCN2 and PKR both in vivo and in vitro, establishing the critical contributions of remote residues to kinase-substrate recognition. In contrast, mutations that blocked translational regulation but not Ser51 phosphorylation impaired the binding of eIF2B to phosphorylated eIF2. Thus, two structurally distinct effectors of eIF2 function, eIF2 kinases and eIF2B, have evolved to recognize the same surface and overlapping determinants on eIF2.

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* Corresponding author. Mailing address: National Institutes of Health, 6 Center Dr., Bethesda, MD 20892-2427. Phone: (301) 496-4519. Fax: (301) 496-8576. E-mail: tdever{at}box-t.nih.gov.

M.D. and B.T. contributed equally to this work.

Present address: Durham College, Oshawa, Ontario L1H 7L7, Canada.

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Molecular and Cellular Biology, April 2005, p. 3063-3075, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3063-3075.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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