Mechanism and Regulation of Protein Synthesis in <i>Saccharomyces cerevisiae</i>

Dever, Thomas E.; Kinzy, Terri Goss; Pavitt, Graham D.

doi:10.1534/genetics.115.186221

Cited by 130 publications

(150 citation statements)

References 484 publications

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“…Amino acid starvation increases the cellular levels of uncharged tRNAs (Staschke et al 2010). These uncharged tRNAs can then bind to a histidyl tRNA synthetase-related domain of the protein kinase, Gcn2, and activate it (Cherkasova and Hinnebusch 2003;Hinnebusch 2005;Castilho et al 2014;Lageix et al 2015;Dever et al 2016). Activated Gcn2 phosphorylates Ser51 of eIF2aP.…”

Section: Candidates To Join Mtorc1 In Cumulative Gln3 Regulationmentioning

confidence: 99%

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General Amino Acid Control and 14-3-3 Proteins Bmh1/2 Are Required for Nitrogen Catabolite Repression-Sensitive Regulation of Gln3 and Gat1 Localization

Tate¹,

Buford²,

Rai³

et al. 2017

Genetics

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Nitrogen catabolite repression (NCR), the ability of Saccharomyces cerevisiae to use good nitrogen sources in preference to poor ones, derives from nitrogen-responsive regulation of the GATA family transcription activators Gln3 and Gat1. In nitrogen-replete conditions, the GATA factors are cytoplasmic and NCR-sensitive transcription minimal. When only poor nitrogen sources are available, Gln3 is nuclear, dramatically increasing GATA factor-mediated transcription. This regulation was originally attributed to mechanistic Tor protein kinase complex 1 (mTorC1)-mediated control of Gln3. However, we recently showed that two regulatory systems act cumulatively to maintain cytoplasmic Gln3 sequestration, only one of which is mTorC1. Present experiments demonstrate that the other previously elusive component is uncharged transfer RNA-activated, Gcn2 protein kinase-mediated general amino acid control (GAAC). Gcn2 and Gcn4 are required for NCR-sensitive nuclear Gln3-Myc 13 localization, and from epistasis experiments Gcn2 appears to function upstream of Ure2. Bmh1/2 are also required for nuclear Gln3-Myc 13 localization and appear to function downstream of Ure2. Overall, Gln3 phosphorylation levels decrease upon loss of Gcn2, Gcn4, or Bmh1/2. Our results add a new dimension to nitrogenresponsive GATA-factor regulation and demonstrate the cumulative participation of the mTorC1 and GAAC pathways, which respond oppositely to nitrogen availability, in the nitrogen-responsive control of catabolic gene expression in yeast.

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Section: Candidates To Join Mtorc1 In Cumulative Gln3 Regulationmentioning

confidence: 99%

“…Nucl.-Cyto., nuclear-cytoplasmic. et al 2015; Dever et al 2016). Active Gcn2 upregulates nuclear Gln3 localization, thereby increasing the cell's ability to maintain the supply of nitrogen precursors required for amino acid biosynthesis in an adverse nitrogen environment.…”

Section: Participation Of Gaac Components Gcn2 and Gcn4mentioning

confidence: 99%

General Amino Acid Control and 14-3-3 Proteins Bmh1/2 Are Required for Nitrogen Catabolite Repression-Sensitive Regulation of Gln3 and Gat1 Localization

Tate¹,

Buford²,

Rai³

et al. 2017

Genetics

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“…Following mRNA selection eIF2 also assists with AUG codon selection during scanning to ensure accurate protein synthesis (1,2). The affinity of eIF2 for Met–tRNA i is dictated by its nucleotide status as eIF2•GTP has high affinity for Met–tRNA i , while eIF2•GDP does not (3).…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with other G protein systems, this additional role for eIF2B is termed a GDI-displacement factor (GDF) function (14). Thus eIF2B GDF activity displaces eIF5 GDI from eIF2•GDP to enable eIF2B GEF and continued rounds of protein synthesis (2,24). …”

Section: Introductionmentioning

confidence: 99%

eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control

Jennings¹,

Kershaw²,

White³

et al. 2016

Nucleic Acids Res

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In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. eIF2 GDP/GTP status is regulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2α phosphorylation in response to diverse signals is a major point of translational control. Here we characterize a growth suppressor mutation in eIF2β that prevents eIF5 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation. By monitoring the binding of fluorescent nucleotides and initiator tRNA to purified eIF2 we show that the eIF2β mutation does not affect intrinsic eIF2 affinities for these ligands, neither does it interfere with eIF2 binding to 43S pre-initiation complex components. Instead we show that the eIF2β mutation prevents eIF5 GDI stabilizing nucleotide binding to eIF2, thereby altering the off-rate of GDP from eIF2•GDP/eIF5 complexes. This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 targets in response to amino acid starvation. These findings provide support for the importance of eIF5 GDI activity in vivo and demonstrate that eIF2β acts in concert with eIF5 to prevent premature release of GDP from eIF2γ and thereby ensure tight control of protein synthesis initiation.

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“…By analyzing polysome profiling fractions and the ribosome protein composition, there are numerous associated non-ribosomal proteins present in addition to ribosomal proteins that fulfill various functions. For example, they can modulate ribosome activity [23]; control the stages during and immediately after translation [25]; act as chaperones that mediate the transfer of ribosomal proteins to their proper sites [26]; interact with newly synthesized polypeptide chains to ensure proper protein folding [27]. To detect non-ribosomal proteins that control ribosome activity, the composition of translationally active and inactive ribosomes was studied in HeLa cells by application of proteomics [23].…”

Section: Strategy To Characterize the Composition Of Active Ribosomesmentioning

confidence: 99%

Exploring ribosome composition and newly synthesized proteins through proteomics and potential biomedical applications

Št́astná

Gottlieb

Eyk

2017

Expert Review of Proteomics

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Introduction: Protein synthesis is the outcome of tightly regulated gene expression which is responsive to a variety of conditions. Efforts are ongoing to monitor individual stages of protein synthesis to ensure maximum efficiency and accuracy. Due to post-transcriptional regulation mechanisms, the correlation between translatome and proteome is higher than between transcriptome and proteome. However, the most accurate approach to assess the key modulators and final protein expression is directly by using proteomics. Areas covered: This review covers various proteomic strategies that were used to better understand post-transcriptional regulation, specifically during and early after translation. The methods that identify both regulatory proteins associated with translational components and newly synthesized proteins are discussed. Expert commentary: Emerging proteomic approaches make it possible to monitor protein dynamics in cells, tissues and whole animals. The ability to detect alteration in protein abundance soon after their synthesis enables earlier recognition of disease causing factors and candidates to prevent/rectify disease phenotype.

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Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

Cited by 130 publications

References 484 publications

General Amino Acid Control and 14-3-3 Proteins Bmh1/2 Are Required for Nitrogen Catabolite Repression-Sensitive Regulation of Gln3 and Gat1 Localization

General Amino Acid Control and 14-3-3 Proteins Bmh1/2 Are Required for Nitrogen Catabolite Repression-Sensitive Regulation of Gln3 and Gat1 Localization

eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control

Exploring ribosome composition and newly synthesized proteins through proteomics and potential biomedical applications

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