Protein Folding at the Exit Tunnel

Fedyukina, Daria V.; Cavagnero, Silvia

doi:10.1146/annurev-biophys-042910-155338

Cited by 95 publications

(90 citation statements)

References 101 publications

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“…Therefore, the release of nascent protein from the ribosome into the cytosol is a slower process (21) than its synthesis. This appears to be consistent with the slow activity gain of nascent protein observed by us (6 -9, 14) and others (22,23). The cohort of chaperones like DnaK, DnaJ, and trigger factor (23) with their exposed hydrophobic patches also provides a unique environment in the cytosol and influences the rate of 50 S subunitmediated protein folding to some extent (17).…”

supporting

confidence: 92%

“…This segmentation seems to be identical for the nascent chain that is being synthesized as well as for chemically unfolded protein containing minimal secondary structure (20,39). The kinetics of folding of the polypeptide chain in the tunnel appears to be slow and postsynthetic as reported by a number of investigators (22,23). It has been reported by Brimacombe and co-worker (11) that the N terminus of the nascent peptide could touch a number of nucleotides in the PTC and finally get back to the PTC before going out of the tunnel through domains IV, III, II, and I.…”

Section: Discussionmentioning

confidence: 62%

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Identical RNA-Protein Interactions in Vivo and in Vitro and a Scheme of Folding the Newly Synthesized Proteins by Ribosomes

Das

Samanta

Hasan

et al. 2012

Journal of Biological Chemistry

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Background: Ribosomal PTC acts as a protein folding modulator in vivo and in vitro. Results: A fixed set of nucleotides in the PTC interacts to fold polypeptides in vivo and in vitro. Conclusion: Folding all proteins through interaction with the same set of nucleotides in PTC implies they have intrinsic homology. Significance: Hundreds of proteins showed an identical cumulative hydrophobicity plot for amino acids.

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supporting

confidence: 92%

Section: Discussionmentioning

confidence: 62%

Identical RNA-Protein Interactions in Vivo and in Vitro and a Scheme of Folding the Newly Synthesized Proteins by Ribosomes

Das

Samanta

Hasan

et al. 2012

Journal of Biological Chemistry

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“…To avoid these potentially dangerous possibilities and facilitate the folding process 2 , a variety of quality control mechanisms are associated with translating ribosomes, including those involving molecular chaperones and other ancillary factors 1 . An additional level of control is provided by the opportunity for proteins to fold during synthesis [3][4][5][6] , thus potentially enhancing folding yields 7 and avoiding misfolded or intermediate species 8,9 . Given its importance, it is not surprising that the cotranslational folding process can be regulated by the modulation of the rates at which successive amino acids are covalently attached to the nascent chain during synthesis.…”

mentioning

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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“…Also analogous to SRP, TF preferentially interacts with hydrophobic sequences on the nascent polypeptide (1,2,4,45,46), mediated by a large concave surface rich in hydrophobic residues (1,(3)(4)(5)(6). Despite these similarities with SRP, TF directs substrate proteins to distinct biogenesis pathways: It exhibits synthetic lethality with DnaK/J and facilitates the productive folding of cytosolic proteins (1,4,7,9,11).…”

mentioning

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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Protein Folding at the Exit Tunnel

Cited by 95 publications

References 101 publications

Identical RNA-Protein Interactions in Vivo and in Vitro and a Scheme of Folding the Newly Synthesized Proteins by Ribosomes

Identical RNA-Protein Interactions in Vivo and in Vitro and a Scheme of Folding the Newly Synthesized Proteins by Ribosomes

Prediction of variable translation rate effects on cotranslational protein folding

Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting

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