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Proofreading through spatial gradients

Galstyan, Vahe and Husain, Kabir and Xiao, Fangzhou and Murugan, Arvind and Phillips, Rob (2020) Proofreading through spatial gradients. eLife, 9 . Art. No. e60415. ISSN 2050-084X. https://resolver.caltech.edu/CaltechAUTHORS:20200526-121021095

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Abstract

Key enzymatic processes use the nonequilibrium error correction mechanism called kinetic proofreading to enhance their specificity. The applicability of traditional proofreading schemes, however, is limited because they typically require dedicated structural features in the enzyme, such as a nucleotide hydrolysis site or multiple intermediate conformations. Here, we explore an alternative conceptual mechanism that achieves error correction by having substrate binding and subsequent product formation occur at distinct physical locations. The time taken by the enzyme–substrate complex to diffuse from one location to another is leveraged to discard wrong substrates. This mechanism does not have the typical structural requirements, making it easier to overlook in experiments. We discuss how the length scales of molecular gradients dictate proofreading performance, and quantify the limitations imposed by realistic diffusion and reaction rates. Our work broadens the applicability of kinetic proofreading and sets the stage for studying spatial gradients as a possible route to specificity.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.7554/eLife.60415DOIArticle
https://doi.org/10.1101/2020.05.23.112664DOIDiscussion Paper
ORCID:
AuthorORCID
Galstyan, Vahe0000-0001-7073-9175
Xiao, Fangzhou0000-0002-5001-5644
Murugan, Arvind0000-0001-5464-917X
Phillips, Rob0000-0003-3082-2809
Additional Information:© 2020 Galstyan et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Received: 26 June 2020; Accepted: 24 December 2020; Published: 24 December 2020. We thank Anatoly Kolomeisky, Shu-ou Shan and Erik Winfree for insightful discussions, Soichi Hirokawa and Avi Flamholz for providing useful feedback on the manuscript. We also thank Alexander Grosberg whose idea of a compartmentalized ‘rotary demon’ motivated the development of our model. This work was supported by the NIH Grant 1R35 GM118043-01, the John Templeton Foundation Grants 51250 and 60973 (to RP), a James S. McDonnell Foundation postdoctoral fellowship (to KH), and the Simons Foundation (AM). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: Vahe Galstyan, Kabir Husain, Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review and editing; Fangzhou Xiao, Conceptualization, Formal analysis, Investigation, Methodology, Writing - review and editing; Arvind Murugan, Rob Phillips, Conceptualization, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing. Data availability: All scripts used to generate the data for making the plots are provided in supporting files.
Funders:
Funding AgencyGrant Number
NIH1R35 GM118043-01
John Templeton Foundation51250
John Templeton Foundation60973
James S. McDonnell FoundationUNSPECIFIED
Simons FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20200526-121021095
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200526-121021095
Official Citation:Proofreading through spatial gradients. eLife 2020;9:e60415; DOI: 10.7554/eLife.60415
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103451
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:26 May 2020 19:31
Last Modified:20 Jan 2021 18:30

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