eIF1A/eIF5B interaction network and its functions in translation initiation complex assembly and remodeling

Nag, Nabanita; Lin, Kueiyu Joshua; Edmonds, Katherine A.; Yu, Jielin; Nadkarni, Devika; Marintcheva, Boriana; Marintchev, Assen

doi:10.1093/nar/gkw552

Cited by 37 publications

(79 citation statements)

References 49 publications

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“…In order to test whether eIF2α-NTD and -CTD interact with each other, we combined NMR chemical shift perturbation (CSP) assays ( 27 , 29 , 30 ) with deletion analysis, comparing peak movements between spectra of full length eIF2α and spectra of eIF2α-NTD and -CTD alone. This approach is effective for observing dynamic interactions ( 28 , 38 ). We collected transverse relaxation optimized spectroscopy heteronuclear single-quantum coherence (TROSY-HSQC) NMR spectra of 2 H/ 15 N-labeled full length eIF2α and its individual domains.…”

Section: Resultsmentioning

confidence: 99%

Novel mechanisms of eIF2B action and regulation by eIF2α phosphorylation

Bogorad

Lin

Marintchev

2017

Nucleic Acids Research

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Eukaryotic translation initiation factor 2 (eIF2) is a heterotrimeric GTPase, which plays a critical role in protein synthesis regulation. eIF2-GTP binds Met-tRNAi to form the eIF2-GTP•Met-tRNAi ternary complex (TC), which is recruited to the 40S ribosomal subunit. Following GTP hydrolysis, eIF2-GDP is recycled back to TC by its guanine nucleotide exchange factor (GEF), eIF2B. Phosphorylation of the eIF2α subunit in response to various cellular stresses converts eIF2 into a competitive inhibitor of eIF2B, which triggers the integrated stress response (ISR). Dysregulation of eIF2B activity is associated with a number of pathologies, including neurodegenerative diseases, metabolic disorders, and cancer. However, despite decades of research, the underlying molecular mechanisms of eIF2B action and regulation remain unknown. Here we employ a combination of NMR, fluorescence spectroscopy, site-directed mutagenesis, and thermodynamics to elucidate the mechanisms of eIF2B action and its regulation by phosphorylation of the substrate eIF2. We present: (i) a novel mechanism for the inhibition of eIF2B activity, whereby eIF2α phosphorylation destabilizes an autoregulatory intramolecular interaction within eIF2α; and (ii) the first structural model for the complex of eIF2B with its substrate, eIF2-GDP, reaction intermediates, apo-eIF2 and eIF2-GTP, and product, TC, with direct implications for the eIF2B catalytic mechanism.

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Section: Resultsmentioning

confidence: 99%

Novel mechanisms of eIF2B action and regulation by eIF2α phosphorylation

Bogorad

Lin

Marintchev

2017

Nucleic Acids Research

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“…A recent study showed downregulation of DUSP10 was associated with HCC metastasis [ 38 ]. EIF5B , one of eukaryotic translation initiation factors, was demonstrated to be involved in cell-cycle arrest in case of up-regulation [ 39 , 40 ]. MNAT1 , a factor of the CDK-activating kinase (CAK) enzymatic complex, is vital to transcription.…”

Section: Discussionmentioning

confidence: 99%

A new risk score based on twelve hepatocellular carcinoma-specific gene expression can predict the patients’ prognosis

Lin

et al. 2018

Aging

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A large panel of molecular biomarkers have been identified to predict the prognosis of hepatocellular carcinoma (HCC), yet with limited clinical application due to difficult extrapolation. We here generated a genetic risk score system comprised of 12 HCC-specific genes to better predict the prognosis of HCC patients. Four genomics profiling datasets (GSE5851, GSE28691, GSE15765 and GSE14323) were searched to seek HCC-specific genes by comparisons between cancer samples and normal liver tissues and between different subtypes of hepatic neoplasms. Univariate survival analysis screened HCC-specific genes associated with overall survival (OS) in the training dataset for next-step risk model construction. The prognostic value of the constructed HCC risk score system was then validated in the TCGA dataset. Stratified analysis indicated this scoring system showed better performance in elderly male patients with HBV infection and preoperative lower levels of creatinine, alpha-fetoprotein and platelet and higher level of albumin. Functional annotation of this risk model in high-risk patients revealed that pathways associated with cell cycle, cell migration and inflammation were significantly enriched. In summary, our constructed HCC-specific gene risk model demonstrated robustness and potentiality in predicting the prognosis of HCC patients, especially among elderly male patients with HBV infection and relatively better general conditions.

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“…Cryo-EM reconstructions of termination- or recycling-related complexes revealed that the NBD-containing core of ABCE1, when bound to ATP, occupies the GTPase-binding center and its FeS cluster domain binds and stabilizes the release factor eRF1 25 or the archaeal mRNA surveillance factor aPelota, 14 respectively. Strikingly, compared with the Pyrococcus abyssi 23 crystal structure, the new tentative model of the m48S IC proposed here indicates that ABCE1 could adopt a novel conformation, unobserved previously, where the NDB binding domains are in a fully closed conformation and the FeS cluster domain is rotated by ∼180° to acquire a proper orientation for direct binding to the 40S h44 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

ABCE1: A special factor that orchestrates translation at the crossroad between recycling and initiation

et al. 2017

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For many years initiation and termination of mRNA translation have been studied separately. However, a direct link between these 2 isolated stages has been suggested by the fact that some initiation factors also control termination and can even promote ribosome recycling; i.e. the last stage where post-terminating 80S ribosomes are split to start a new round of initiation. Notably, it is now firmly established that, among other factors, ribosomal recycling critically requires the NTPase ABCE1. However, several earlier reports have proposed that ABCE1 also somehow participates in the initiation complex assembly. Based on an extended analysis of our recently published late-stage 48S initiation complex from rabbit, here we provide new mechanistic insights into this putative role of ABCE1 in initiation. This point of view represents the first structural evidence in which the regulatory role of the recycling factor ABCE1 in initiation is discussed and establishes a corner stone for elucidating the interplay between ABCE1 and several initiation factors during the transit from ribosomal recycling to formation of the elongation competent 80S initiation complex.

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eIF1A/eIF5B interaction network and its functions in translation initiation complex assembly and remodeling

Cited by 37 publications

References 49 publications

Novel mechanisms of eIF2B action and regulation by eIF2α phosphorylation

Novel mechanisms of eIF2B action and regulation by eIF2α phosphorylation

A new risk score based on twelve hepatocellular carcinoma-specific gene expression can predict the patients’ prognosis

ABCE1: A special factor that orchestrates translation at the crossroad between recycling and initiation

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