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Molecular and Cellular Biology, June 2000, p. 3965-3976, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of Domains and Residues within the epsilon  Subunit of Eukaryotic Translation Initiation Factor 2B (eIF2Bepsilon ) Required for Guanine Nucleotide Exchange Reveals a Novel Activation Function Promoted by eIF2B Complex Formation

Edith Gomez and Graham D. Pavitt*

Department of Anatomy and Physiology, Medical Sciences Institute, University of Dundee, Dundee, United Kingdom

Received 18 January 2000/Accepted 15 March 2000

Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor for protein synthesis initiation factor 2 (eIF2). Composed of five subunits, it converts eIF2 from a GDP-bound form to the active eIF2-GTP complex. This is a regulatory step of translation initiation. In vitro, eIF2B catalytic function can be provided by the largest (epsilon) subunit alone (eIF2Bvarepsilon ). This activity is stimulated by complex formation with the other eIF2B subunits. We have analyzed the roles of different regions of eIF2Bvarepsilon in catalysis, in eIF2B complex formation, and in binding to eIF2 by characterizing mutations in the Saccharomyces cerevisiae gene encoding eIF2Bvarepsilon (GCD6) that impair the essential function of eIF2B. Our analysis of nonsense mutations indicates that the C terminus of eIF2Bvarepsilon (residues 518 to 712) is required for both catalytic activity and interaction with eIF2. In addition, missense mutations within this region impair the catalytic activity of eIF2Bvarepsilon without affecting its ability to bind eIF2. Internal, in-frame deletions within the N-terminal half of eIF2Bvarepsilon disrupt eIF2B complex formation without affecting the nucleotide exchange activity of eIF2Bvarepsilon alone. Finally, missense mutations identified within this region do not affect the catalytic activity of eIF2Bvarepsilon alone or its interactions with the other eIF2B subunits or with eIF2. Instead, these missense mutations act indirectly by impairing the enhancement of the rate of nucleotide exchange that results from complex formation between eIF2Bvarepsilon and the other eIF2B subunits. This suggests that the N-terminal region of eIF2Bvarepsilon is an activation domain that responds to eIF2B complex formation.

* Corresponding author. Mailing address: MSI/WTB Complex, University of Dundee, Dundee, DD1 5EH, United Kingdom. Phone: (44) 1382-344898. Fax: (44) 1382-345507. E-mail: g.d.pavitt{at}dundee.ac.uk.

Molecular and Cellular Biology, June 2000, p. 3965-3976, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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