1. Computational and Systems Biology
  2. Microbiology and Infectious Disease
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A covariation analysis reveals elements of selectivity in quorum sensing systems

  1. Samantha Wellington Miranda
  2. Qian Cong
  3. Amy L Schaefer
  4. Emily Kenna MacLeod
  5. Angelina Zimenko
  6. David Baker
  7. E Peter Greenberg  Is a corresponding author
  1. University of Washington, United States
  2. University of Texas Southwestern Medical Center, United States
  3. University of Washington School of Medicine, United States
Research Article
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Cite this article as: eLife 2021;10:e69169 doi: 10.7554/eLife.69169

Abstract

Many bacteria communicate with kin and coordinate group behaviors through a form of cell-cell signaling called acyl-homoserine lactone (AHL) quorum sensing (QS). In these systems, a signal synthase produces an AHL to which its paired receptor selectively responds. Selectivity is fundamental to cell signaling. Despite its importance, it has been challenging to determine how this selectivity is achieved and how AHL QS systems evolve and diversify. We hypothesized that we could use covariation within the protein sequences of AHL synthases and receptors to identify selectivity residues. We began by identifying about 6,000 unique synthase-receptor pairs. We then used the protein sequences of these pairs to identify covariation patterns and mapped the patterns onto the LasI/R system from Pseudomonas aeruginosa PAO1. The covarying residues in both proteins cluster around the ligand-binding sites. We demonstrate that these residues are involved in system selectivity toward the cognate signal and go on to engineer the Las system to both produce and respond to an alternate AHL signal. We have thus demonstrated that covariation methods provide a powerful approach for investigating selectivity in protein-small molecule interactions and have deepened our understanding of how communication systems evolve and diversify.

Data availability

All data generated or analyzed during this study are include in the manuscript and supporting files. Source data files have been provided for the protein sequences analyzed and for Figure 6, Figure 4 - figure supplement 2, Figure 5 - figure supplement 1, and Figure 7 - figure supplement 2.

Article and author information

Author details

  1. Samantha Wellington Miranda

    Microbiology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5072-2608
  2. Qian Cong

    Eugene McDermott Center for Human Growth and Development; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8909-0414
  3. Amy L Schaefer

    Microbiology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  4. Emily Kenna MacLeod

    Microbiology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  5. Angelina Zimenko

    Microbiology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  6. David Baker

    Biochemistry, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7896-6217
  7. E Peter Greenberg

    Department of Microbiology, University of Washington School of Medicine, Seattle, United States
    For correspondence
    epgreen@u.washington.edu
    Competing interests
    E Peter Greenberg, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9474-8041

Funding

National Institutes of Health (R35GM136218)

  • E Peter Greenberg

National Institutes of Health (Program Grant,P41 GM103533-24)

  • Qian Cong

Washington Research Foundation (Postdoctoral Fellowship)

  • Qian Cong

Helen Hay Whitney Foundation (Postdoctoral Fellowship)

  • Samantha Wellington Miranda

Howard Hughes Medical Institute (Investigator Program)

  • David Baker

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

Reviewing Editor

  1. Michael T Laub, Massachusetts Institute of Technology, United States

Publication history

  1. Received: April 6, 2021
  2. Accepted: June 25, 2021
  3. Accepted Manuscript published: June 28, 2021 (version 1)

Copyright

© 2021, Wellington Miranda 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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