Cotranslational protein folding—fact or fiction?

Deane, Charlotte M.; Dong, Mingqiang; Huard, Fabien P.E.; Lance, Braddon K.; Wood, Graham R.

doi:10.1093/bioinformatics/btm175

Cited by 29 publications

(24 citation statements)

References 20 publications

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“…Further analysis that considered topological accessibility (the ability of a protein to fold from a given residue as a starting point using only local contacts) found this to be more evident towards the N-terminus in the α / β class of proteins [59]. In a similar vein, Deane et al [60] developed a measure of previous contacts which assesses the extent to which the chain forms contacts with previously extruded residues. They also found that the α / β class and ancient folds [61] exhibited such evidence of cotranslation.…”

Section: Introductionmentioning

confidence: 99%

Directionality in protein fold prediction

et al. 2010

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BackgroundEver since the ground-breaking work of Anfinsen et al. in which a denatured protein was found to refold to its native state, it has been frequently stated by the protein fold prediction community that all the information required for protein folding lies in the amino acid sequence. Recent in vitro experiments and in silico computational studies, however, have shown that cotranslation may affect the folding pathway of some proteins, especially those of ancient folds. In this paper aspects of cotranslational folding have been incorporated into a protein structure prediction algorithm by adapting the Rosetta program to fold proteins as the nascent chain elongates. This makes it possible to conduct a pairwise comparison of folding accuracy, by comparing folds created sequentially from each end of the protein.ResultsA single main result emerged: in 94% of proteins analyzed, following the sense of translation, from N-terminus to C-terminus, produced better predictions than following the reverse sense of translation, from the C-terminus to N-terminus. Two secondary results emerged. First, this superiority of N-terminus to C-terminus folding was more marked for proteins showing stronger evidence of cotranslation and second, an algorithm following the sense of translation produced predictions comparable to, and occasionally better than, Rosetta.ConclusionsThere is a directionality effect in protein fold prediction. At present, prediction methods appear to be too noisy to take advantage of this effect; as techniques refine, it may be possible to draw benefit from a sequential approach to protein fold prediction.

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Section: Introductionmentioning

confidence: 99%

Directionality in protein fold prediction

et al. 2010

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“…Various considerations have been put forward to explain these surface preferences of protein termini, several of them invoking co-translational protein folding [3–8]. In particular, Krishna and Englander [5] noted that

“ An apparent functional rationale for two-state folding, with the initial barrier being rate-limiting, is that it avoids the prolonged occupation of collapsed partially folded states that would expose proteins to unwanted intermolecular aggregation and proteolysis.

…”

Section: Resultsmentioning

confidence: 99%

“…Although the question of co-translational protein folding has been intensely studied in recent years (reviewed in [8–11]), the anchoring of distal parts of the protein, and the possible role of such anchoring in protein chain twisting, has not been given much attention. We now discuss the features of the peptidyl transferase reaction and the properties of ribosome-associated factors that may play essential roles in these processes.…”

Section: Resultsmentioning

confidence: 99%

Rotational restriction of nascent peptides as an essential element of co-translational protein folding: possible molecular players and structural consequences

Sorokina¹,

Mushegian²

2017

Biol Direct

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BackgroundA basic tenet of protein science is that all information about the spatial structure of proteins is present in their sequences. Nonetheless, many proteins fail to attain native structure upon experimental denaturation and refolding in vitro, raising the question of the specific role of cellular machinery in protein folding in vivo. Recently, we hypothesized that energy-dependent twisting of the protein backbone is an unappreciated essential factor guiding the protein folding process in vivo. Torque force may be applied by the ribosome co-translationally, and when accompanied by simultaneous restriction of the rotational mobility of the distal part of the growing chain, the resulting tension in the protein backbone would facilitate the formation of local secondary structure and direct the folding process.ResultsOur model of the early stages of protein folding in vivo postulates that the free motion of both terminal regions of the protein during its synthesis and maturation is restricted. The long-known but unexplained phenomenon of statistical overrepresentation of protein termini on the surfaces of the protein structures may be an indication of the backbone twist-based folding mechanism; sustained maintenance of a twist requires that both ends of the protein chain are anchored in space, and if the ends are released only after the majority of folding is complete, they are much more likely to remain on the surface of the molecule. We identified the molecular components that are likely to play a role in the twisting of the nascent protein chain and in the anchoring of its N-terminus. The twist may be induced at the C-terminus of the nascent polypeptide by the peptidyltransferase center of the ribosome. Several ribosome-associated proteins, including the trigger factor in bacteria and the nascent polypeptide-associated complex in archaea and eukaryotes, may restrict the rotational mobility of the N-proximal regions of the peptides.ConclusionsMany experimental observations are consistent with the hypothesis of co-translational twisting of the protein backbone. Several molecular players in this hypothetical mechanism of protein folding can be suggested. In addition, the new view of protein folding in vivo opens the possibility of novel potential drug targets to combat human protein folding diseases.ReviewersThis article was reviewed by Lakshminarayan Iyer and István Simon.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-017-0186-1) contains supplementary material, which is available to authorized users.

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“…Currently, not only is the existence of a protein exit tunnel commonly accepted it is also well established that this tunnel possesses dynamic features [40,51] which enable it to play active roles in the sequence-specific arrest of nascent chains in response to the cellular signals [52,53] and in controlling the operational mode of the translocon at the ER membrane [54]. Fluorescence resonance energy transfer (FRET) measurements [54,55] and computational analyses [56][57][58] have indicated that some extent of protein folding may happen within the ribosome exit tunnel. In support to these findings, a crevice adjacent to the tunnel wall that can provide space for co-translational transient folding has been identified [59], thus hinting at intratunnel ribosomal chaperon activity.…”

Section: The Ribosome Tunnel: From the Ptc To The External Cellular Ementioning

confidence: 99%

Ribosome's mode of function: myths, facts and recent results

Wekselman

Davidovich

Agmon

et al. 2008

Journal of Peptide Science

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Ribosomes translate the genetic code into proteins in all living cells with extremely high efficiency, owing to their inherent flexibility and to their spectacular architecture. During the last 6 decades, extensive effort has been made to elucidate the molecular mechanisms associated with their function, and a quantum jump has been made in recent years, once the three dimensional structures of ribosomes and their functional complexes have been determined. These illuminated key issues in ribosome function, confirmed various biochemical, genetic, and medical findings, and revealed mechanistic details beyond previous expectation, thus leading to conceptual revolutions, and turning old myths into actual facts.

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Cotranslational protein folding—fact or fiction?

Cited by 29 publications

References 20 publications

Directionality in protein fold prediction

Directionality in protein fold prediction

Rotational restriction of nascent peptides as an essential element of co-translational protein folding: possible molecular players and structural consequences

Ribosome's mode of function: myths, facts and recent results

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