Statics of the ribosomal exit tunnel: implications for cotranslational peptide folding, elongation regulation, and antibiotics binding.
A sophisticated interplay between the static properties of the ribosomal exit tunnel and its functional role in cotranslational processes is revealed by constraint counting on topological network representations of large ribosomal subunits from four different organisms. As for the global flexibility characteristics of the subunit, the results demonstrate a conserved stable structural environment of the tunnel. The findings render unlikely that deformations of the tunnel move peptides down the tunnel in an active manner. Furthermore, the stable environment rules out that the tunnel can adapt widely so as to allow tertiary folding of nascent chains. Nevertheless, there are local zones of flexible nucleotides within the tunnel, between the peptidyl transferase center and the tunnel constriction, and at the tunnel exit. These flexible zones strikingly agree with previously identified folding zones. As for cotranslational elongation regulation, flexible residues in the beta-hairpin of the ribosomal L22 protein were verified, as suggested previously based on structural results. These results support the hypothesis that L22 can undergo conformational changes that regulate the tunnel voyage of nascent polypeptides. Furthermore, rRNA elements, for which conformational changes have been observed upon interaction of the tunnel wall with a nascent SecM peptide, are less strongly coupled to the subunit core. Sequences of coupled rigid clusters are identified between the tunnel and some of these elements, suggesting signal transmission by a domino-like mechanical coupling. Finally, differences in the flexibility of the glycosidic bonds of bases that form antibiotics-binding crevices within the peptidyl transferase center and the tunnel region are revealed for ribosomal structures from different kingdoms. In order to explain antibiotics selectivity, action, and resistance, according to these results, differences in the degrees of freedom of the binding regions may need to be considered.
Fulle
Simone
S
Department of Biological Sciences, Molecular Bioinformatics Group, Goethe University, Frankfurt, Germany.
Gohlke
Holger
H
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D019614:Haloarcula marismortui / Q000378:metabolism; D008958:Models, Molecular; D010441:Peptide Chain Elongation, Translational; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D010458:Peptidyl Transferases / Q000378:metabolism; D018583:Pliability; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021381:Protein Transport; D012269:Ribosomal Proteins / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry*; D015398:Signal Transduction
D000900:Anti-Bacterial Agents; D010455:Peptides; D012269:Ribosomal Proteins; C056368:ribosomal protein L4; D010458:Peptidyl Transferases