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Multi-site rate control analysis identifies ribosomal scanning as the sole high-capacity/low-flux-control step in mRNA translation

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Firczuk, Helena, Teahan, James, Mendes, Pedro and McCarthy, John E. G. (2020) Multi-site rate control analysis identifies ribosomal scanning as the sole high-capacity/low-flux-control step in mRNA translation. FEBS Journal, 287 (5). pp. 925-940. doi:10.1111/febs.15059 ISSN 1742-4658.

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Official URL: https://doi.org/10.1111/febs.15059

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Abstract

Control of complex intracellular pathways such as protein synthesis is critical to organism survival, but is poorly understood. Translation of a reading frame in eukaryotic mRNA is preceded by a scanning process in which a subset of translation factors helps guide ribosomes to the start codon. Here, we perform comparative analysis of the control status of this scanning step that sits between recruitment of the small ribosomal subunit to the m7GpppG‐capped 5′end of mRNA and of the control exerted by downstream phases of polypeptide initiation, elongation and termination. We have utilized a detailed predictive model as guidance for designing quantitative experimental interrogation of control in the yeast translation initiation pathway. We have built a synthetic orthogonal copper‐responsive regulatory promoter (PCuR3) that is used here together with the tet07 regulatory system in a novel dual‐site in vivo rate control analysis strategy. Combining this two‐site strategy with calibrated mass spectrometry to determine translation factor abundance values, we have tested model‐based predictions of rate control properties of the in vivo system. We conclude from the results that the components of the translation machinery that promote scanning collectively function as a low‐flux‐control system with a capacity to transfer ribosomes into the core process of polypeptide production that exceeds the respective capacities of the steps of polypeptide initiation, elongation and termination. In contrast, the step immediately prior to scanning, that is, ribosome recruitment via the mRNA 5′ cap‐binding complex, is a high‐flux‐control step.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
Q Science > QR Microbiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Proteins -- Synthesis, Ribosomes, Polypeptides, Yeast -- Analysis, Messenger RNA
Journal or Publication Title: FEBS Journal
Publisher: Blackwell
ISSN: 1742-4658
Official Date: March 2020
Dates:
DateEvent
March 2020Published
13 September 2019Available
9 September 2019Accepted
Volume: 287
Number: 5
Page Range: pp. 925-940
DOI: 10.1111/febs.15059
Status: Peer Reviewed
Publication Status: Published
Reuse Statement (publisher, data, author rights): "This is the peer reviewed version of the following article: Firczuk, H., Teahan, J., Mendes, P. and McCarthy, J.E. (2019), Multisite rate control analysis identifies ribosomal scanning as the sole high‐capacity/low‐flux‐control step in mRNA translation. FEBS J., which has been published in final form at https://doi.org/10.1111/febs.15059. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 13 September 2019
Date of first compliant Open Access: 13 September 2020
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/1008349/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/1020535/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
GM080219National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
GM080219National Institute of General Medical Scienceshttp://dx.doi.org/10.13039/100000057
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