A peptide deformylase–ribosome complex reveals mechanism of nascent chain processing

Bingel-Erlenmeyer, R.; Köhler, Rebecca; Sandikci, Arzu; Antolić, Snježana; Maier, Timm; Schaffitzel, Christiane; Wiedmann, Brigitte; Bukau, Bernd; Ban, Nenad

doi:10.1038/nature06683

Cited by 101 publications

(103 citation statements)

References 36 publications

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“…τ F,i and τ D,i are the average times of folding and unfolding at nascent chain length i on an arrested RNC. The placement of the first residue (i = 1) in the P-site of the ribosome, corresponding to fmet-tRNA in prokaryotes 27 , is designated as time point zero, t 1 0 = 0 s, and the time at which the ith residue is added is t i…”

Section: Resultsmentioning

confidence: 99%

Prediction of variable translation rate effects on cotranslational protein folding

2012

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The concomitant folding of a protein with its synthesis on the ribosome is influenced by a number of different timescales including the translation rate. Here we present a kinetic formalism to describe cotranslational folding and predict the effects of variable translation rates on this process. our approach, which utilizes equilibrium data from arrested ribosome nascent chain complexes, provides domain folding probabilities in quantitative agreement with molecular simulations of folding at different translation rates. We show that the effects of single codon mutations in messenger RnA that alter the translation rate can lead to a dramatic increase in the extent of folding under specific conditions. The kinetic formalism that we discuss can describe the cotranslational folding process occurring on a single ribosome molecule as well as for a collection of stochastically translating ribosomes.

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Section: Resultsmentioning

confidence: 99%

Prediction of variable translation rate effects on cotranslational protein folding

2012

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“…In E. coli the same ribosomal surface area that is formed by Rpl17 and Rpl31 in yeast is built up by L22 (the homolog of Rpl17) and L32/L17 (unique to eubacteria). Indeed, the co-translationally acting enzyme peptide deformylase, which removes the formyl group from the starter methionine of the nascent chain is anchored via a basic C-terminal ␣-helix between L22 and L32 (12). Future studies will have to assess what molecular details determine which factor binds to this second universal docking site or whether they can simultaneously engage the ribosome.…”

Section: Discussionmentioning

confidence: 99%

Dual Binding Mode of the Nascent Polypeptide-associated Complex Reveals a Novel Universal Adapter Site on the Ribosome

Pech

Spreter

Beckmann

et al. 2010

Journal of Biological Chemistry

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Nascent polypeptide-associated complex (NAC) was identified in eukaryotes as the first cytosolic factor that contacts the nascent polypeptide chain emerging from the ribosome. NAC is present as a homodimer in archaea and as a highly conserved heterodimer in eukaryotes. Mutations in NAC cause severe embryonically lethal phenotypes in mice, Drosophila melanogaster, and Caenorhabditis elegans. In the yeast Saccharomyces cerevisiae NAC is quantitatively associated with ribosomes. Here we show that NAC contacts several ribosomal proteins. The N terminus of ␤NAC, however, specifically contacts near the tunnel exit ribosomal protein Rpl31, which is unique to eukaryotes and archaea. Moreover, the first 23 amino acids of ␤NAC are sufficient to direct an otherwise non-associated protein to the ribosome. In contrast, ␣NAC (Egd2p) contacts Rpl17, the direct neighbor of Rpl31 at the ribosomal tunnel exit site. Rpl31 was also recently identified as a contact site for the SRP receptor and the ribosome-associated complex. Furthermore, in Escherichia coli peptide deformylase (PDF) interacts with the corresponding surface area on the eubacterial ribosome. In addition to the previously identified universal adapter site represented by Rpl25/Rpl35, we therefore refer to Rpl31/Rpl17 as a novel universal docking site for ribosome-associated factors on the eukaryotic ribosome.

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“…Accurate selection of the nascent protein into the correct biogenesis pathway is essential to maintain the homeostasis of the proteome. In recent years, there has been an increasing number of structures of individual protein biogenesis factors bound to the ribosome exit site (3,18,26,56,(66)(67)(68)(69)(70)(71)(72)(73)(74), as well as efforts to globally catalog the nascent polypeptides they occupy (9, 13). However, the key question remains: Given the crowded environment at the ribosome exit site and a limited time window of action, how does a nascent polypeptide engage the correct set of factors and hence commit to its correct biogenesis pathway?…”

Section: Discussionmentioning

confidence: 99%

Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting

Ariosa

Lee

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The ribosome exit site is a crowded environment where numerous factors contact nascent polypeptides to influence their folding, localization, and quality control. Timely and accurate selection of nascent polypeptides into the correct pathway is essential for proper protein biogenesis. To understand how this is accomplished, we probe the mechanism by which nascent polypeptides are accurately sorted between the major cotranslational chaperone trigger factor (TF) and the essential cotranslational targeting machinery, signal recognition particle (SRP). We show that TF regulates SRP function at three distinct stages, including binding of the translating ribosome, membrane targeting via recruitment of the SRP receptor, and rejection of ribosome-bound nascent polypeptides beyond a critical length. Together, these mechanisms enhance the specificity of substrate selection into both pathways. Our results reveal a multilayered mechanism of molecular interplay at the ribosome exit site, and provide a conceptual framework to understand how proteins are selected among distinct biogenesis machineries in this crowded environment.signal recognition particle | trigger factor | ribosome | protein biogenesis | GTPases P roper protein biogenesis is a prerequisite for the maintenance of a functional proteome. Accumulating data indicate that this process begins at the ribosome exit site, where many protein biogenesis machineries can interact and gain access to the nascent polypeptide. This includes chaperones (1-5) such as trigger factor (TF) (1, 4, 6, 7), Hsp70, and the nascent polypeptide-associated complex (8-13); modification enzymes (10, 14-16) such as N-acetyl transferase, methionine aminopeptidase, and arginyl transferase; protein-targeting and translocation machineries such as signal recognition particle (SRP) (17-20), SecA (21), the SecYEG (or Sec61p) (22, 23) and YidC translocases (24,25), and the ribosome-bound quality control complex (26)(27)(28)(29)(30). Engagement of these factors with nascent polypeptides influences their folding, assembly, localization, processing, and quality control. Within seconds after the nascent polypeptide emerges from the ribosomal exit tunnel, it must engage the correct set of factors and thus commit to the proper biogenesis pathway. How this is accomplished in the crowded environment at the ribosome exit site is an emerging question. In this work, we address this question by deciphering how nascent proteins are selected between two major protein biogenesis machineries in bacteria, SRP and TF.SRP is a universally conserved ribonucleoprotein complex responsible for the cotranslational targeting of proteins to the eukaryotic endoplasmic reticulum (ER), or the bacterial plasma membrane (31). SRP recognizes ribosome-nascent chain complexes (termed RNC or cargo) carrying strong signal sequences and delivers them to the SecYEG or YidC translocation machinery on the target membrane. SRP binds RNC via two interactions: a helical N domain in the SRP54 protein (called Ffh in bacteria) binds the ribosoma...

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A peptide deformylase–ribosome complex reveals mechanism of nascent chain processing

Cited by 101 publications

References 36 publications

Prediction of variable translation rate effects on cotranslational protein folding

Prediction of variable translation rate effects on cotranslational protein folding

Dual Binding Mode of the Nascent Polypeptide-associated Complex Reveals a Novel Universal Adapter Site on the Ribosome

Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting

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