scholarly journals The shape of the bacterial ribosome exit tunnel affects cotranslational protein folding

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Renuka Kudva ◽  
Pengfei Tian ◽  
Fátima Pardo-Avila ◽  
Marta Carroni ◽  
Robert B Best ◽  
...  
Keyword(s):  
Protein Folding ◽  
Protein Domain ◽  
Coarse Grained ◽  
E Coli ◽  
Folded Structure ◽  
Bacterial Ribosome ◽  
Folded Proteins ◽  
Exit Tunnel ◽  
Ribosome Exit Tunnel ◽  
Dynamics Simulations

The E. coli ribosome exit tunnel can accommodate small folded proteins, while larger ones fold outside. It remains unclear, however, to what extent the geometry of the tunnel influences protein folding. Here, using E. coli ribosomes with deletions in loops in proteins uL23 and uL24 that protrude into the tunnel, we investigate how tunnel geometry determines where proteins of different sizes fold. We find that a 29-residue zinc-finger domain normally folding close to the uL23 loop folds deeper in the tunnel in uL23 Δloop ribosomes, while two ~ 100 residue proteins normally folding close to the uL24 loop near the tunnel exit port fold at deeper locations in uL24 Δloop ribosomes, in good agreement with results obtained by coarse-grained molecular dynamics simulations. This supports the idea that cotranslational folding commences once a protein domain reaches a location in the exit tunnel where there is sufficient space to house the folded structure.

scholarly journals The Shape of the Bacterial Ribosome Exit Tunnel Affects Cotranslational Protein Folding

2018 ◽  
Author(s):  
Renuka Kudva ◽  
Pengfei Tian ◽  
Fatima Pardo Avila ◽  
Marta Carroni ◽  
Robert B. Best ◽  
...  
Keyword(s):  
Protein Folding ◽  
Protein Domain ◽  
Coarse Grained ◽  
E Coli ◽  
Folded Structure ◽  
Bacterial Ribosome ◽  
Folded Proteins ◽  
Exit Tunnel ◽  
Ribosome Exit Tunnel ◽  
Dynamics Simulations

AbstractThe E.coli ribosome exit tunnel can accommodate small folded proteins, while larger ones fold outside. It remains unclear, however, to what extent the geometry of the tunnel influences protein folding. Here, using E. coli ribosomes with deletions in loops in proteins uL23 and uL24 that protrude into the tunnel, we investigate how tunnel geometry determines where proteins of different sizes fold. We find that a 29-residue zinc-finger domain normally folding close to the uL23 loop folds deeper in the tunnel in uL23 Δloop ribosomes, while two ~100-residue protein normally folding close to the uL24 loop near the tunnel exit port fold at deeper locations in uL24 Δloop ribosomes, in good agreement with results obtained by coarse-grained molecular dynamics simulations. This supports the idea that cotranslational folding commences once a protein domain reaches a location in the exit tunnel where there is sufficient space to house the folded structure.

scholarly journals Author response: The shape of the bacterial ribosome exit tunnel affects cotranslational protein folding

2018 ◽  
Author(s):  
Renuka Kudva ◽  
Pengfei Tian ◽  
Fátima Pardo-Avila ◽  
Marta Carroni ◽  
Robert B Best ◽  
...  
Keyword(s):  
Protein Folding ◽  
Author Response ◽  
Bacterial Ribosome ◽  
Exit Tunnel ◽  
Ribosome Exit Tunnel

scholarly journals Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bertrand Beckert ◽  
Elodie C. Leroy ◽  
Shanmugapriya Sothiselvam ◽  
Lars V. Bock ◽  
Maxim S. Svetlov ◽  
...  
Keyword(s):  
Antibiotic Resistance Genes ◽  
Structural Basis ◽  
Sequence Motifs ◽  
Specific Sequence ◽  
Bacterial Ribosome ◽  
Translational Arrest ◽  
Exit Tunnel ◽  
Mechanistic Basis ◽  
Dynamics Simulations ◽  
Context Specific

AbstractMacrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.

scholarly journals Cotranslational Protein Folding inside the Ribosome Exit Tunnel

Cell Reports ◽  
2015 ◽  
Vol 12 (10) ◽  
pp. 1533-1540 ◽  
Author(s):  
Ola B. Nilsson ◽  
Rickard Hedman ◽  
Jacopo Marino ◽  
Stephan Wickles ◽  
Lukas Bischoff ◽  
...  
Keyword(s):  
Protein Folding ◽  
Exit Tunnel ◽  
Ribosome Exit Tunnel

scholarly journals The ribosome and its role in protein folding: looking through a magnifying glass

2017 ◽  
Vol 73 (6) ◽  
pp. 509-521 ◽  
Author(s):  
Abid Javed ◽  
John Christodoulou ◽  
Lisa D. Cabrita ◽  
Elena V. Orlova
Keyword(s):  
Protein Folding ◽  
Structural Biology ◽  
Polypeptide Chain ◽  
Structure And Function ◽  
Cellular Activity ◽  
Cryo Electron Microscopy ◽  
Nascent Chain ◽  
Exit Tunnel ◽  
Dynamics Simulations ◽  
And Function

Protein folding, a process that underpins cellular activity, begins co-translationally on the ribosome. During translation, a newly synthesized polypeptide chain enters the ribosomal exit tunnel and actively interacts with the ribosome elements – the r-proteins and rRNA that line the tunnel – prior to emerging into the cellular milieu. While understanding of the structure and function of the ribosome has advanced significantly, little is known about the process of folding of the emerging nascent chain (NC). Advances in cryo-electron microscopy are enabling visualization of NCs within the exit tunnel, allowing early glimpses of the interplay between the NC and the ribosome. Once it has emerged from the exit tunnel into the cytosol, the NC (still attached to its parent ribosome) can acquire a range of conformations, which can be characterized by NMR spectroscopy. Using experimental restraints within molecular-dynamics simulations, the ensemble of NC structures can be described. In order to delineate the process of co-translational protein folding, a hybrid structural biology approach is foreseeable, potentially offering a complete atomic description of protein folding as it occurs on the ribosome.

Protein folds: towards understanding folding from inspection of native structures

1995 ◽  
Vol 348 (1323) ◽  
pp. 71-79 ◽  
Keyword(s):  
Protein Folding ◽  
Protein Structure ◽  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Protein Domain ◽  
Major Influence ◽  
Protein Topology ◽  
Protein Folds ◽  
Short Summary ◽  
Folded Proteins

Following a short summary of some of the principal features of folded proteins, the results of two complementary studies of protein structure are presented, the first concerned with the factors which influence secondary structure propensity and the second an analysis of protein topology. In an attempt to deconvolute the physical contributions to secondary structure propensities, we have calculated intrinsic ɸ,ψ propensities, derived from the coil regions of proteins. Comparison of intrinsic ɸ,ψ propensities with their equivalent secondary structure values show correlations for both helix and strand. This suggests that the local dipeptide, steric and electrostatic interactions have a major influence on secondary structure propensity. We then proceed to inspect the distribution of protein domain folds observed to date. Several folds occur very commonly, so that 46% of the current non-homologous database comprises only nine folds. The implications of these results for protein folding are discussed.

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