Tunnel Vision: Insights from Biochemical and Biophysical Studies

Deutsch, Carol

doi:10.1007/978-4-431-55052-5_4

Cited by 9 publications

(12 citation statements)

References 138 publications

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“…It appears that another translocase, ClpX, operates in a similar force regime (20, 21). Given that a number of polypeptide sequences are known to stall the ribosome (3, 22–24), our results suggest that force can play a generally important role as a regulator of elongation. In instances where ribosome–nascent chain interactions are less robust than the SecM system, folding could play an important role in modulating translation elongation and vice versa.…”

mentioning

confidence: 76%

“…Such rate variations may be required for proper folding and processing of nascent proteins (1). Moreover, interactions of specific nascent chain sequences (2, 3) with the ribosome exit tunnel (4) result in reduced rates of elongation. The bacterial SecM protein represents an example of a stalling sequence that interacts with the ribosome exit tunnel and allosterically represses the peptidyl transferase activity of the ribosome (4–7).…”

mentioning

confidence: 99%

“…We wondered whether folding of a nascent globular protein domain could generate a force capable of modulating elongation by acting on peptide-tunnel interactions. Such interactions could serve to tune elongation rates to folding transitions (3, 4). The exit tunnel is too narrow to accommodate folded protein domains (17); therefore, as a nascent polypeptide emerges from the exit tunnel and folds in close proximity to the ribosome, it will be sterically excluded from the tunnel.…”

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confidence: 99%

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Mechanical force releases nascent chain–mediated ribosome arrest in vitro and in vivo

Goldman

Kaiser

Milin

et al. 2015

Science

225

320

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Protein synthesis rates can affect gene expression and the folding and activity of the translation product. Interactions between the nascent polypeptide and the ribosome exit tunnel represent one mode of regulating synthesis rates. The SecM protein arrests its own translation, and release of arrest at the translocon has been proposed to occur by mechanical force. Using optical tweezers, we demonstrate that arrest of SecM-stalled ribosomes can indeed be rescued by force alone and that the force needed to release stalling can be generated in vivo by a nascent chain folding near the ribosome tunnel exit. We formulate a kinetic model describing how a protein can regulate its own synthesis by the force generated during folding, tuning ribosome activity to structure acquisition by a nascent polypeptide.

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confidence: 76%

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confidence: 99%

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confidence: 99%

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Mechanical force releases nascent chain–mediated ribosome arrest in vitro and in vivo

Goldman

Kaiser

Milin

et al. 2015

Science

225

320

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“…At the other end, the exit port, the elongating nascent chain emerges. In between, the nascent peptide begins to fold 1–11 . The tunnel, made of rRNA, some protein, water, and ions, plays an active role in early protein folding 12–14 .…”

Section: Introductionmentioning

confidence: 99%

Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel

Delaney

Gamper

et al. 2017

Journal of Molecular Biology

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All proteins are synthesized by the ribosome, a macromolecular complex that accomplishes the life-sustaining tasks of faithfully decoding mRNA and catalyzing peptide bond formation at the peptidyl transferase center (PTC). The ribosome has evolved an exit tunnel to host the elongating new peptide, protect it from proteolytic digestion, and guide its emergence. It is here that the nascent chain begins to fold. This folding process depends on the rate of translation at the PTC. We report here that, besides PTC events, translation kinetics depend on steric constraints on nascent peptide side chains, and that confined movements of cramped side chains within and through the tunnel fine-tune elongation rates.

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“…The subunits have different functional properties in translation, while they function together as a complex (Ramakrishnan, 2002;Schmeing and Ramakrishnan, 2009). The large subunit 50S catalyzes peptide bond synthesis at the highly conserved catalytic cavity peptidyl transferase center (PTC), where nucleotides G2251, G2252, A2451, C2452, U2506, U2585, A2602 play critical roles in the translation process (Polacek et al, 2003;Youngman et al, 2004;Erlacher et al, 2005;Martin Schmeing et al, 2005;Long et al, 2006;Selmer et al, 2006;Amort et al, 2007;Deutsch, 2014). The nascent polypeptide chain attached to the peptidyl-tRNA (P-tRNA) grows through the ∼100 Å long ribosomal tunnel.…”

Section: Introductionmentioning

confidence: 99%

Exploring Allosteric Signaling in the Exit Tunnel of the Bacterial Ribosome by Molecular Dynamics Simulations and Residue Network Model

Guzel

Yildirim

Yuce

et al. 2020

Front. Mol. Biosci.

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The bacterial ribosomal tunnel is equipped with numerous sites highly sensitive to the course of the translation process. This study investigates allosteric pathways linking distant functional sites that collaboratively play a role either in translation regulation or recruitment of chaperones. We apply perturbation response scanning (PRS) analysis to 700 ns long and 500 ns long coarse-grained molecular dynamics simulations of E. coli and T. thermophilus large subunits, respectively, to reveal nucleotides/residues with the ability to transmit perturbations by dynamic rationale. We also use the residue network model with the k-shortest pathways method to calculate suboptimal pathways based on the contact topology of the ribosomal tunnel of E. coli crystal structure and 101 ClustENM generated conformers of T. thermophilus large subunit. In the upper part of the tunnel, results suggest that A2062 and A2451 can communicate in both directions for translation stalling, mostly through dynamically coupled C2063, C2064, and A2450. For a similar purpose, U2585 and U2586 are coupled with A2062, while they are also sensitive to uL4 and uL22 at the constriction region through two different pathways at the opposite sides of the tunnel wall. In addition, the constriction region communicates with the chaperone binding site on uL23 at the solvent side but through few nucleotides. Potential allosteric communication pathways between the lower part of the tunnel and chaperone binding site mostly use the flexible loop of uL23, while A1336-G1339 provide a suboptimal pathway. Both species seem to employ similar mechanisms in the long tunnel, where a non-conserved cavity at the bacterial uL23 and 23S rRNA interface is proposed as a novel drug target.

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Tunnel Vision: Insights from Biochemical and Biophysical Studies

Cited by 9 publications

References 138 publications

Mechanical force releases nascent chain–mediated ribosome arrest in vitro and in vivo

Mechanical force releases nascent chain–mediated ribosome arrest in vitro and in vivo

Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel

Exploring Allosteric Signaling in the Exit Tunnel of the Bacterial Ribosome by Molecular Dynamics Simulations and Residue Network Model

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