scholarly journals 4E-BP is a target of the GCN2–ATF4 pathway during Drosophila development and aging

2016 ◽  
Vol 216 (1) ◽  
pp. 115-129 ◽  
Author(s):  
Min-Ji Kang ◽  
Deepika Vasudevan ◽  
Kwonyoon Kang ◽  
Kyunggon Kim ◽  
Jung-Eun Park ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Normal Development ◽  
Mrna Translation ◽  
Model Organisms ◽  
Metabolic Labeling ◽  
Amino Acid Availability ◽  
Development And Aging ◽  
Development Analysis ◽  
Translational Inhibitor

Reduced amino acid availability attenuates mRNA translation in cells and helps to extend lifespan in model organisms. The amino acid deprivation–activated kinase GCN2 mediates this response in part by phosphorylating eIF2α. In addition, the cap-dependent translational inhibitor 4E-BP is transcriptionally induced to extend lifespan in Drosophila melanogaster, but through an unclear mechanism. Here, we show that GCN2 and its downstream transcription factor, ATF4, mediate 4E-BP induction, and GCN2 is required for lifespan extension in response to dietary restriction of amino acids. The 4E-BP intron contains ATF4-binding sites that not only respond to stress but also show inherent ATF4 activity during normal development. Analysis of the newly synthesized proteome through metabolic labeling combined with click chemistry shows that certain stress-responsive proteins are resistant to inhibition by 4E-BP, and gcn2 mutant flies have reduced levels of stress-responsive protein synthesis. These results indicate that GCN2 and ATF4 are important regulators of 4E-BP transcription during normal development and aging.

scholarly journals Translational regulation in response to changes in amino acid availability in Neurospora crassa.

1995 ◽  
Vol 15 (10) ◽  
pp. 5235-5245 ◽  
Author(s):  
Z Luo ◽  
M Freitag ◽  
M S Sachs
Keyword(s):  
Amino Acid ◽  
Neurospora Crassa ◽  
Translational Regulation ◽  
Mrna Translation ◽  
Small Subunit ◽  
Negative Regulation ◽  
Start Codon ◽  
Mrna Levels ◽  
Carbamoyl Phosphate ◽  
Amino Acid Availability

We examined the regulation of Neurospora crassa arg-2 and cpc-1 in response to amino acid availability.arg-2 encodes the small subunit of arginine-specific carbamoyl phosphate synthetase; it is subject to unique negative regulation by Arg and is positively regulated in response to limitation for many different amino acids through a mechanism known as cross-pathway control. cpc-1 specifies a transcriptional activator important for crosspathway control. Expression of these genes was compared with that of the cytochrome oxidase subunit V gene, cox-5. Analyses of mRNA levels, polypeptide pulse-labeling results, and the distribution of mRNA in polysomes indicated that Arg-specific negative regulation of arg-2 affected the levels of both arg-2 mRNA and arg-2 mRNA translation. Negative translational effects on arg-2 and positive translational effects on cpc-1 were apparent soon after cells were provided with exogenous Arg. In cells limited for His, increased expression of arg-2 and cpc-1, and decreased expression of cox-5, also had translational and transcriptional components. The arg-2 and cpc-1 transcripts contain upstream open reading frames (uORFs), as do their Saccharomyces cerevisiae homologs CPA1 and GCN4. We examined the regulation of arg-2-lacZ reporter genes containing or lacking the uORF start codon; the capacity for arg-2 uORF translation appeared critical for controlling gene expression.

scholarly journals Transcriptional Autoregulation and Inhibition of mRNA Translation of Amino Acid Regulator GenecpcAof Filamentous FungusAspergillus nidulans

2001 ◽  
Vol 12 (9) ◽  
pp. 2846-2857 ◽  
Author(s):  
Bernd Hoffmann ◽  
Oliver Valerius ◽  
Meike Andermann ◽  
Gerhard H. Braus
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Level ◽  
Mrna Level ◽  
Point Mutations ◽  
Mrna Translation ◽  
Transcriptional Activator ◽  
Regulatory Elements ◽  
Amino Acid Availability ◽  
Starvation Conditions

The CPCA protein of the filamentous fungus Aspergillus nidulans is a member of the c-Jun-like transcriptional activator family. It acts as central transcription factor of the cross-pathway regulatory network of amino acid biosynthesis and is functionally exchangeable for the general control transcriptional activator Gcn4p of Saccharomyces cerevisiae. In contrast to GCN4, expression of cpcA is strongly regulated by two equally important mechanisms with additive effects that lead to a fivefold increased CPCA protein amount under amino acid starvation conditions. One component of cpcA regulation involves a transcriptional autoregulatory mechanism via a CPCA recognition element (CPRE) in the cpcA promoter that causes a sevenfold increased cpcA mRNA level when cells are starved for amino acids. Point mutations in the CPRE cause a constitutively low mRNA level of cpcA and a halved protein level when amino acids are limited. Moreover, two upstream open reading frames (uORFs) in the 5′ region of thecpcA mRNA are important for a translational regulatory mechanism. Destruction of both short uORFs results in a sixfold increased CPCA protein level under nonstarvation conditions and a 10-fold increase under starvation conditions. Mutations in both the CPRE and uORF regulatory elements lead to an intermediate effect, with a low cpcA mRNA level but a threefold increased CPCA protein level independent of amino acid availability. These data argue for a combined regulation of cpcA that includes a translational regulation like that of yeast GCN4 as well as a transcriptional regulation like that of the mammalianjun and fos genes.

scholarly journals Paip1 Interacts with Poly(A) Binding Protein through Two Independent Binding Motifs

2002 ◽  
Vol 22 (11) ◽  
pp. 3769-3782 ◽  
Author(s):  
Guylaine Roy ◽  
Gregory De Crescenzo ◽  
Kianoush Khaleghpour ◽  
Avak Kahvejian ◽  
Maureen O'Connor-McCourt ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Binding Protein ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Rna Recognition Motifs ◽  
Eukaryotic Mrnas ◽  
Amino Acid Stretch ◽  
Recognition Motifs ◽  
Eukaryotic Initiation Factor 4G

ABSTRACT The 3′ poly(A) tail of eukaryotic mRNAs plays an important role in the regulation of translation. The poly(A) binding protein (PABP) interacts with eukaryotic initiation factor 4G (eIF4G), a component of the eIF4F complex, which binds to the 5′ cap structure. The PABP-eIF4G interaction brings about the circularization of the mRNA by joining its 5′ and 3′ termini, thereby stimulating mRNA translation. The activity of PABP is regulated by two interacting proteins, Paip1 and Paip2. To study the mechanism of the Paip1-PABP interaction, far-Western, glutathione S-transferase pull-down, and surface plasmon resonance experiments were performed. Paip1 contains two binding sites for PABP, PAM1 and PAM2 (for PABP-interacting motifs 1 and 2). PAM2 consists of a 15-amino-acid stretch residing in the N terminus, and PAM1 encompasses a larger C-terminal acidic-amino-acid-rich region. PABP also contains two Paip1 binding sites, one located in RNA recognition motifs 1 and 2 and the other located in the C-terminal domain. Paip1 binds to PABP with a 1:1 stoichiometry and an apparent Kd of 1.9 nM.

Predicting the Strength of Stacking Interactions Between Heterocycles and Aromatic Amino Acid Side Chains

2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Analise C. Doney ◽  
Steven Wheeler
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Side Chains ◽  
Stacking Interactions ◽  
Inhibitor Binding ◽  
Protein Binding Sites ◽  
Amino Acid Side Chains

<p>Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous <i>ab initio</i> data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.</p>

Combined effect of citrulline and lactoserum on amino acid availability in aged rats

Nutrition ◽  
2021 ◽  
Vol 87-88 ◽  
pp. 111196
Author(s):  
Prasanthi Jegatheesan ◽  
Christel Vicente ◽  
Perrine Marquet de Rouge ◽  
Nathalie Neveux ◽  
Radji Ramassamy ◽  
...  
Keyword(s):  
Amino Acid ◽  
Combined Effect ◽  
Aged Rats ◽  
Amino Acid Availability
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