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PMID:15126500

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Citation

Sattlegger, E, Swanson, MJ, Ashcraft, EA, Jennings, JL, Fekete, RA, Link, AJ and Hinnebusch, AG (2004) YIH1 is an actin-binding protein that inhibits protein kinase GCN2 and impairs general amino acid control when overexpressed. J. Biol. Chem. 279:29952-62

Abstract

The general amino acid control (GAAC) enables yeast cells to overcome amino acid deprivation by activation of the alpha subunit of translation initiation factor 2 (eIF2alpha) kinase GCN2 and consequent induction of GCN4, a transcriptional activator of amino acid biosynthetic genes. Binding of GCN2 to GCN1 is required for stimulation of GCN2 kinase activity by uncharged tRNA in starved cells. Here we show that YIH1, when overexpressed, dampens the GAAC response (Gcn- phenotype) by suppressing eIF2alpha phosphorylation by GCN2. The overexpressed YIH1 binds GCN1 and reduces GCN1-GCN2 complex formation, and, consistent with this, the Gcn- phenotype produced by YIH1 overexpression is suppressed by GCN2 overexpression. YIH1 interacts with the same GCN1 fragment that binds GCN2, and this YIH1-GCN1 interaction requires Arg-2259 in GCN1 in vitro and in full-length GCN1 in vivo, as found for GCN2-GCN1 interaction. However, deletion of YIH1 does not increase eIF2alpha phosphorylation or derepress the GAAC, suggesting that YIH1 at native levels is not a general inhibitor of GCN2 activity. We discovered that YIH1 normally resides in a complex with monomeric actin, rather than GCN1, and that a genetic reduction in actin levels decreases the GAAC response. This Gcn- phenotype was partially suppressed by deletion of YIH1, consistent with YIH1-mediated inhibition of GCN2 in actin-deficient cells. We suggest that YIH1 resides in a YIH1-actin complex and may be released for inhibition of GCN2 and stimulation of protein synthesis under specialized conditions or in a restricted cellular compartment in which YIH1 is displaced from monomeric actin.

Links

PubMed Online version:10.1074/jbc.M404009200

Keywords

Actins/chemistry; Actins/metabolism; Alleles; Amino Acids/chemistry; Arginine/chemistry; DNA-Binding Proteins/metabolism; Eukaryotic Initiation Factor-2/metabolism; Galactose/chemistry; Gene Deletion; Genotype; Glutathione Transferase/metabolism; Mass Spectrometry; Microfilament Proteins/chemistry; Microfilament Proteins/physiology; Peptide Elongation Factors; Phenotype; Phosphorylation; Plasmids/metabolism; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein Binding; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases; RNA, Transfer/metabolism; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins/chemistry; Saccharomyces cerevisiae Proteins/metabolism; Saccharomyces cerevisiae Proteins/physiology; Transcriptional Activation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

YEAST:YIH1

enables

GO:0003785: actin monomer binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P60010

F

Seeded From UniProt

complete

YEAST:YIH1

involved_in

GO:0031333: negative regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:YIH1

involved_in

GO:0034198: cellular response to amino acid starvation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:YIH1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P33892

F

Seeded From UniProt

complete

YEAST:YIH1

enables

GO:0003785: actin monomer binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

YEAST:YIH1

involved_in

GO:0001933: negative regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:YIH1

enables

GO:0004860: protein kinase inhibitor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

YEAST:GCN1

involved_in

GO:0034198: cellular response to amino acid starvation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:GCN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25637

F

Seeded From UniProt

complete

YEAST:ACT

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25637

F

Seeded From UniProt

complete


See also

References

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