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Nascent polypeptide within the exit tunnel stabilizes the ribosome to counteract risky translation

ABSTRACT: Nascent polypeptide within the exit tunnel stabilizes the ribosome to counteract risky translation

PROVIDER: PRJNA764085 | ENA |

REPOSITORIES: ENA

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Nascent polypeptide within the exit tunnel stabilizes the ribosome to counteract risky translation

Project description:Continuous translation elongation, irrespective of amino acid sequences, is a prerequisite for living organisms to produce their proteomes. However, the risk of elongation abortion is concealed within nascent polypeptide products. For example, negatively charged sequences with occasional intermittent prolines, termed intrinsic ribosome destabilization (IRD) sequences, destabilizes the translating ribosomal complex. Thus, some nascent chain sequences lead to premature translation cessation. Here, we show that most potential IRD sequences in the middle of open reading frames remain cryptic by two mechanisms: the nascent polypeptide itself that spans the exit tunnel and its bulky amino acid residues that occupy the tunnel entrance region. Thus, nascent polypeptide products have a built-in ability to ensure elongation continuity by serving as a bridge and thus by protecting the large and small ribosomal subunits from dissociation.

2021-12-08 | GSE184331 | GEO

Pol5 is required for recycling of small subunit biogenesis factors and for formation of the polypeptide exit tunnel of the large ribosomal subunit

Project description:More than 200 assembly factors (AFs) are required for the production of ribosomes in yeast. The stepwise association and dissociation of these AFs with the pre-ribosomal subunits occurs in a strictly hierarchical manner to ensure correct maturation of the pre-rRNAs and assembly of the ribosomal proteins. Although decades of research have provided a wealth of insights into the functions of many AFs, others remain poorly characterized. Pol5 was initially classified with B-type DNA polymerases, however, several lines of evidence indicate the involvement of this protein in ribosome assembly. Here, we show that depletion of Pol5 affects the processing of pre-rRNAs destined for the both the large and small subunits. Furthermore, we identify binding sites for Pol5 in the 5’ external transcribed spacer and within domain III of the 25S rRNA sequence. Consistent with this, we reveal that Pol5 is required for recruitment of ribosomal proteins that form the polypeptide exit tunnel in the LSU and that depletion of Pol5 impairs the release of 5’ ETS fragments from early pre-40S particles. The dual functions of Pol5 in 60S assembly and recycling of pre-40S AFs suggest that this factor could contribute to ensuring the stoichiometric production of ribosomal subunits.

2019-11-05 | GSE132973 | GEO

Cysteine oxidation and disulfide formation in the ribosomal exit tunnel

Project description:Understanding the conformational sampling of translation-arrested ribosome nascent chain complexes is key to understand co-translational folding. Up to now, coupling of cysteine oxidation, disulfide bond formation and structure formation in nascent chains has remained elusive. Here, we investigate the eye-lens protein γB-crystallin in the ribosomal exit tunnel. Using mass spectrometry, theoretical simulations, dynamic nuclear polarization-enhanced solid-state nuclear magnetic resonance and cryo-electron microscopy, we show that thiol groups of cysteine residues undergo S-glutathionylation and S-nitrosylation and form non-native disulfide bonds. Thus, covalent modification chemistry occurs already prior to nascent chain release as the ribosome exit tunnel provides sufficient space even for disulfide bond formation which can guide protein folding.

2020-11-09 | PXD021574 | Pride

Pol5 is required for recycling of small subunit biogenesis factors and for formation of the polypeptide exit tunnel of the large ribosomal subunit

Project description:Pol5 is required for recycling of small subunit biogenesis factors and for formation of the polypeptide exit tunnel of the large ribosomal subunit

| PRJNA549607 | ENA

Protein synthesis in the developing neocortex at near-atomic resolution reveals Ebp1-mediated neuronal proteostasis at the 60S tunnel exit

Project description:Proteostasis must be finely tuned in the nervous system, as it represents an essential feature of neurodevelopment, and dominant pathology in neurodegenerative disease. At the gateway of proteostasis is the ribosome; however, the architecture of ribosomal complexes in the developing mammalian brain has not been visualized. In this study, we analyze the molecular architecture of ex vivo embryonic and perinatal mouse neocortical ribosomes, revealing Ebp1 as a 60S peptide tunnel exit binding factor at near-atomic resolution by multiparticle cryo-electron microscopy. The impact of Ebp1 on the neuronal proteome was analyzed by pSILAC and BONCAT coupled mass spectrometry, implicating Ebp1 in neurite outgrowth proteostasis, with in vivo embryonic Ebp1 knockdown resulting in neurite outgrowth dysregulation. This study constitutes the first near-atomic resolution structure of actively translating ribosomes ex vivo from the nervous system, and visualizes Ebp1 as a chaperone of protein synthesis at the 60S peptide tunnel exit in neocortical neurogenesis.

2021-01-04 | PXD014740 | Pride

Protein synthesis in the developing neocortex at near-atomic resolution reveals Ebp1-mediated neuronal proteostasis at the 60S tunnel exit

2021-01-04 | PXD014841 | Pride

Ribosome profiling reveals sequence-independent post-initiation pausing as a signature of translation

Project description:The journey of a newly synthesized polypeptide starts in the peptidyltransferase center of the ribosome, from where it traverses the exit tunnel. The interior of the ribosome exit tunnel is neither straight nor smooth. How the ribosome dynamics in vivo is influenced by the exit tunnel is poorly understood. Genome-wide ribosome profiling in mammalian cells reveals elevated ribosome density at the start codon and surprisingly the downstream 5th codon position as well. We found that the highly focused ribosomal pausing shortly after initiation is attributed to the geometry of the exit tunnel, as deletion of the loop region from ribosome protein L4 diminishes translational pausing at the 5th codon position. Unexpectedly, the ribosome variant undergoes translational abandonment shortly after initiation, suggesting that there exists an obligatory step between initiation and elongation commitment. We propose that the post-initiation pausing of ribosomes represents an inherent signature of the translation machinery to ensure productive translation.

2021-02-17 | GSE166874 | GEO

Proteins at the polypeptide tunnel exit of the yeast mitochondrial ribosome.

Project description: Not available

| S-EPMC2885179 | biostudies-literature

Structural insights into assembly of the ribosomal nascent polypeptide exit tunnel.

Project description: Not available

| S-EPMC7547690 | biostudies-literature

A molecular network of conserved factors keeps ribosomes dormant in the egg

Project description:Ribosomes are produced in large quantities during oogenesis and stored in the egg. However, the egg and early embryo are translationally inactive. How translation is activated during embryogenesis is poorly understood. Using mass-spectrometry and cryo-EM analyses of ribosomes isolated from zebrafish and Xenopus eggs and embryos, we find that ribosomes transition from a dormant to an active state during the first hours of embryogenesis. Dormant ribosomes are associated with four factors that form two modules: a Habp4-eEF2 module that stabilizes ribosome levels and a Dap1b/Dapl1-eIF-5a module that represses translation. Dap/Dap1b is a newly discovered translational inhibitor that stably inserts into the polypeptide exit tunnel. Thus, a developmentally programmed, unique ribosome state plays a key role in ribosome storage and translational repression in the egg.

2022-11-03 | PXD026866 | Pride

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