Proofreading through spatial gradients

  1. Vahe Galstyan
  2. Kabir Husain
  3. Fangzhou Xiao
  4. Arvind Murugan  Is a corresponding author
  5. Rob Phillips  Is a corresponding author
  1. California Institute of Technology, United States
  2. University of Chicago, United States

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 since 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.

Data availability

All scripts used to generate the data for making the plots are provided in supporting files.

Article and author information

Author details

  1. Vahe Galstyan

    Biochemistry and Molecular Biophysics, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7073-9175
  2. Kabir Husain

    Department of Physics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Fangzhou Xiao

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Arvind Murugan

    Department of Physics, University of Chicago, Chicago, United States
    For correspondence
    amurugan@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5464-917X
  5. Rob Phillips

    Department of Bioengineering, California Institute of Technology, Pasadena, United States
    For correspondence
    phillips@pboc.caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3082-2809

Funding

James S. McDonnell Foundation

  • Kabir Husain

Simons Foundation

  • Arvind Murugan

John Templeton Foundation

  • Rob Phillips

National Institute of General Medical Sciences

  • Rob Phillips

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ahmet Yildiz, University of California, Berkeley, United States

Publication history

  1. Received: June 26, 2020
  2. Accepted: December 24, 2020
  3. Accepted Manuscript published: December 24, 2020 (version 1)
  4. Version of Record published: January 18, 2021 (version 2)

Copyright

© 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.

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  1. Vahe Galstyan
  2. Kabir Husain
  3. Fangzhou Xiao
  4. Arvind Murugan
  5. Rob Phillips
(2020)
Proofreading through spatial gradients
eLife 9:e60415.
https://doi.org/10.7554/eLife.60415
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