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Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides

Zimmer, Matthew H. and Niesen, Michiel J. M. and Miller, Thomas F., III (2021) Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides. Biophysical Journal . ISSN 0006-3495. doi:10.1016/j.bpj.2021.03.041. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20201021-082852041

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Abstract

Force-sensitive arrest peptides regulate protein biosynthesis by stalling the ribosome as they are translated. Synthesis can be resumed when the nascent arrest peptide experiences a pulling force of sufficient magnitude to break the stall. Efficient stalling is dependent on the specific identity of a large number of amino acids, including amino acids which are tens of angstroms away from the peptidyl transferase center (PTC). The mechanism of force-induced restart and the role of these essential amino acids far from the PTC is currently unknown. We use hundreds of independent molecular dynamics trajectories spanning over 120 μs in combination with kinetic analysis to characterize multiple barriers along the force-induced restart pathway for the arrest peptide SecM. We find that the essential amino acids far from the PTC play a major role in controlling the transduction of applied force. In successive states along the stall-breaking pathway, the applied force propagates up the nascent chain until it reaches the C-terminus of SecM and the PTC, inducing conformational changes that allow for restart of translation. A similar mechanism of force propagation through multiple states is observed in the VemP stall-breaking pathway, but secondary structure in VemP allows for heterogeneity in the order of transitions through intermediate states. Results from both arrest peptides explain how residues that are tens of angstroms away from the catalytic center of the ribosome impact stalling efficiency by mediating the response to an applied force and shielding the amino acids responsible for maintaining the stalled state of the PTC.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.bpj.2021.03.041DOIArticle
https://doi.org/10.1101/2020.10.16.342899DOIDiscussion Paper
ORCID:
AuthorORCID
Zimmer, Matthew H.0000-0002-1437-2636
Niesen, Michiel J. M.0000-0002-9255-6203
Miller, Thomas F., III0000-0002-1882-5380
Additional Information:© 2021 Biophysical Society. Received 2 November 2020, Accepted 19 March 2021, Available online 29 April 2021. Anton 2 computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D.E. Shaw Research. This work was also supported by a grant from NIGMS, National Institutes of Health, (R01GM125063) to TFM and MZ. Author Contributions: All authors contributed to the design of the research. MHZ performed the simulations and processed data. All authors analyzed the results and wrote the manuscript.
Funders:
Funding AgencyGrant Number
NIHR01GM116961
NIHR01GM125063
DOI:10.1016/j.bpj.2021.03.041
Record Number:CaltechAUTHORS:20201021-082852041
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201021-082852041
Official Citation:Matthew H. Zimmer, Michiel JM. Niesen, Thomas F. Miller, Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides, Biophysical Journal, 2021, ISSN 0006-3495, https://doi.org/10.1016/j.bpj.2021.03.041. (https://www.sciencedirect.com/science/article/pii/S0006349521003350)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106181
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Oct 2020 16:30
Last Modified:03 May 2021 19:44

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