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GENES & DEVELOPMENT 21:1217-1230, 2007
©2007 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo

Yuen-Nei Cheung1, David Maag2, Sarah F. Mitchell2, Christie A. Fekete1, Mikkel A. Algire2, Julie E. Takacs2, Nikolay Shirokikh3, Tatyana Pestova3, Jon R. Lorsch2,5, and Alan G. Hinnebusch1,4

1 Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA; 2 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 3 Department of Microbiology and Immunology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203, USA

Selection of the AUG start codon is a key step in translation initiation requiring hydrolysis of GTP in the eIF2•GTP•Met-tRNAiMet ternary complex (TC) and subsequent Pi release from eIF2•GDP•Pi. It is thought that eIF1 prevents recognition of non-AUGs by promoting scanning and blocking Pi release at non-AUG codons. We show that Sui– mutations in Saccharomyces cerevisiae eIF1, which increase initiation at UUG codons, reduce interaction of eIF1 with 40S subunits in vitro and in vivo, and both defects are diminished in cells by overexpressing the mutant proteins. Remarkably, Sui– mutation ISQLG93–97ASQAA (abbreviated 93–97) accelerates eIF1 dissociation and Pi release from reconstituted preinitiation complexes (PICs), whereas a hyperaccuracy mutation in eIF1A (that suppresses Sui– mutations) decreases the eIF1 off-rate. These findings demonstrate that eIF1 dissociation is a critical step in start codon selection, which is modulated by eIF1A. We also describe Gcd– mutations in eIF1 that impair TC loading on 40S subunits or destabilize the multifactor complex containing eIF1, eIF3, eIF5, and TC, showing that eIF1 promotes PIC assembly in vivo beyond its important functions in AUG selection.

[Keywords: AUG selection; Saccharomyces cerevisiae; translation initiation; eIF1]

Received January 5, 2007; revised version accepted March 19, 2007.

4 Corresponding authors.

E-MAIL ahinnebusch{at}nih.gov; FAX (301) 496-6828.

5 E-MAIL jlorsch{at}jhmi.edu; FAX (410) 955-0637.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1528307


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