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J. Biol. Chem., Vol. 277, Issue 34, 30675-30683, August 23, 2002
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From the Protein kinase GCN2 regulates translation
initiation by phosphorylating eukaryotic initiation factor 2
Serine 577 Is Phosphorylated and Negatively Affects the tRNA
Binding and eIF2
Kinase Activities of GCN2*
§,§,,,,,
, and**
Laboratory of Gene Regulation and
Development, NICHD, National Institutes of Health, Bethesda, Maryland
20892 and the ¶ Laboratory of Biophysical Chemistry, NHLBI,
National Institutes of Health, Bethesda, Maryland 20892
(eIF2), impeding general protein synthesis but specifically inducing
translation of GCN4, a transcriptional activator of amino
acid biosynthetic genes in Saccharomyces cerevisiae. GCN2
activity is stimulated in amino acid-deprived cells through binding of
uncharged tRNA to a domain related to histidyl tRNA synthetase. We show
that GCN2 is phosphorylated by another kinase on serine 577, located N-terminal to the kinase domain. Mutation of Ser-577 to alanine produced partial activation of GCN2 in nonstarved cells, increasing the
level of phosphorylated eIF2, derepressing GCN4
expression, and elevating the cellular levels of tryptophan and
histidine. The Ala-577 mutation also increased the tRNA binding
affinity of purified GCN2, which can account for the elevated kinase
activity of GCN2-S577A in nonstarved cells where uncharged tRNA levels are low. Whereas Ser-577 remains phosphorylated in amino acid-starved cells, its dephosphorylation could mediate GCN2 activation in other
stress or starvation conditions by lowering the threshold of uncharged
tRNA required to activate the protein.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Verna and Mars McLean Dept. of Biochemistry
and Molecular Biology, Baylor College of Medicine Houston, TX 77030.
**
To whom correspondence should be addressed: National Institutes of
Health, Bldg. 6A, Rm. B1A13, Bethesda, MD 20892. Tel.: 301-496-4480;
E-mail: ahinnebusch@nih.gov.
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