Transmembrane but not soluble helices fold inside the ribosome tunnel

Bañó‐Polo, Manuel; Baeza-Delgado, Carlos; Tamborero, Silvia; Hazel, Anthony; Grau, Brayan; Im, Nilsson; Whitley, Paul; Gumbart, James C.; Heijne, Gunnar von; Mingarro, Ismael

doi:10.1038/s41467-018-07554-7

Cited by 41 publications

(44 citation statements)

References 59 publications

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“…However, not every polypeptide chain that ultimately adopts helical conformation starts folding inside the peptide exit tunnel. The overall hydrophobicity, propensity to form an α-helix, and the element length are the major determinants of α-helix formation within the tunnel [63]. Indeed, accessibility assays, FRET, and molecular dynamics simulations provide evidence that transmembrane helices favor early compaction during translation to a much larger extent than their soluble counterparts [40,63,64].…”

Section: Folding Inside the Exit Tunnelmentioning

confidence: 99%

Cotranslational Folding of Proteins on the Ribosome

2020

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Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence suggests that the ribosome can alter the folding trajectory in many different ways. In this review, we summarize the recent examples of how translation affects folding of single-domain, multiple-domain and oligomeric proteins. The vectorial nature of translation, the spatial constraints of the exit tunnel, and the electrostatic properties of the ribosome-nascent peptide complex define the onset of early folding events. The ribosome can facilitate protein compaction, induce the formation of intermediates that are not observed in solution, or delay the onset of folding. Examples of single-domain proteins suggest that early compaction events can define the folding pathway for some types of domain structures. Folding of multi-domain proteins proceeds in a domain-wise fashion, with each domain having its role in stabilizing or destabilizing neighboring domains. Finally, the assembly of protein complexes can also begin cotranslationally. In all these cases, the ribosome helps the nascent protein to attain a native fold and avoid the kinetic traps of misfolding.

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Section: Folding Inside the Exit Tunnelmentioning

confidence: 99%

Cotranslational Folding of Proteins on the Ribosome

2020

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“…In the case of transmembrane helical proteins, this effect has led to the proposal of a "twostage model" [9,10], in which the individual helices are first inserted into the membrane, before assembling to their native structure. In the cell, the analogous insertion process is usually accomplished by the translocon machinery [11,12].…”

Section: Introductionmentioning

confidence: 99%

Atomistic mechanism of transmembrane helix association

et al. 2020

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Transmembrane helix association is a fundamental step in the folding of helical membrane proteins. The prototypical example of this association is formation of the glycophorin dimer. While its structure and stability have been well-characterized experimentally, the detailed assembly mechanism is harder to obtain. Here, we use all-atom simulations within phospholipid membrane to study glycophorin association. We find that initial association results in the formation of a non-native intermediate, separated by a significant free energy barrier from the dimer with a native binding interface. We have used transition-path sampling to determine the association mechanism. We find that the mechanism of the initial bimolecular association to form the intermediate state can be mediated by many possible contacts, but seems to be particularly favoured by formation of non-native contacts between the C-termini of the two helices. On the other hand, the contacts which are key to determining progression from the intermediate to the native state are those which define the native binding interface, reminiscent of the role played by native contacts in determining folding of globular proteins. As a check on the simulations, we have computed association and dissociation rates from the transition-path sampling. We obtain results in reasonable accord with available experimental data, after correcting for differences in native state stability. Our results yield an atomistic description of the mechanism for a simple prototype of helical membrane protein folding.

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“…Indeed, experiments investigating helix formation inside the ribosome tunnel demonstrated that hydrophobic transmembrane protein sequences form compacted structures inside the tunnel, suggesting the formation of an α -helix. 11…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, the helicity does not increase upon substitution of serine with alanine for D ≥ 14.9 Å However, each VSV-G protein sequence formed a helix within the center of the sequence and this is consistent with prior studies. 11…”

Section: Resultsmentioning

confidence: 99%

Water-mediated interactions determine helix formation of peptides in open nanotubes

Suvlu

Thirumalai

Rasaiah

2020

Preprint

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Water-mediated interactions (WMIs) play diverse roles in molecular biology. They are particularly relevant in geometrically confined spaces such as the interior of the chaperonin, at the interface between ligands and their binding partners, and in the ribosome tunnel. Inspired in part by the geometry of the ribosome tunnel, we consider confinement effects on the stability of peptides. We describe results from replica exchange molecular dynamics simulations of a system containing a 23-alanine or 23-serine polypeptide confined to non-polar and polar nanotubes in the gas phase and when open to a water reservoir. We quantify the effect of water in determining the preferred conformational states of these polypeptides by calculating the difference in the solvation free energy for the helix and coil states in the open nanotube in the two phases. Our simulations reveal several possibilities. We find that nanoscopic confinement preferentially stabilizes the helical state of polypeptides with hydrophobic side chains, which is explained by the entropic stabilization mechanism proposed on the basis of polymer physics. Polypeptide chains with hydrophilic side chains can adopt helical structures within nanotubes, but helix formation is sensitive to the nature of the nanotube due to WMIs. We elaborate on the potential implications of our findings to the stability of peptides in the ribosome tunnel.

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Transmembrane but not soluble helices fold inside the ribosome tunnel

Cited by 41 publications

References 59 publications

Cotranslational Folding of Proteins on the Ribosome

Cotranslational Folding of Proteins on the Ribosome

Atomistic mechanism of transmembrane helix association

Water-mediated interactions determine helix formation of peptides in open nanotubes

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