Functional and structural segregation of overlapping helices in HIV-1

  1. Maliheh Safari
  2. Bhargavi Jayaraman
  3. Shumin Yang
  4. Cynthia Smith
  5. Jason D Fernandes  Is a corresponding author
  6. Alan D Frankel  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Scribe Therapeutics, United States

Abstract

Overlapping coding regions balance selective forces between multiple genes. One possible division of nucleotide sequence is that the predominant selective force on a particular nucleotide can be attributed to just one gene. While this arrangement has been observed in regions in which one gene is structured and the other is disordered, we sought to explore how overlapping genes balance constraints when both protein products are structured over the same sequence. We use a combination of sequence analysis, functional assays and selection experiments to examine an overlapped region in HIV-1 that encodes helical regions in both Env and Rev. We find that functional segregation occurs even in this overlap, with each protein spacing its functional residues in a manner that allows a mutable non-binding face of one helix to encode important functional residues on a charged face in the other helix. Additionally, our experiments reveal novel and critical functional residues in Env and have implications for the therapeutic targeting of HIV-1.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE179046Code is available on https://github.com/jferna10/EnvPaper. All graphs were generated inRstudio with associated files available on github and/or in Supplementary Tables.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Maliheh Safari

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Bhargavi Jayaraman

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    Bhargavi Jayaraman, is currently an employee at Synthekine. The author has no financial interests to declare regarding this work..
  3. Shumin Yang

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Cynthia Smith

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Jason D Fernandes

    Molecular Engineering, Scribe Therapeutics, Alameda, United States
    For correspondence
    jason@scribetx.com
    Competing interests
    Jason D Fernandes, is an employee of Scribe Therapeutics. The author has no financial interests to declare regarding this work..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8625-1796
  6. Alan D Frankel

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    frankel@cgl.ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2525-9508

Funding

National Institute of Allergy and Infectious Diseases (P50AI150476)

  • Alan D Frankel

National Institute of General Medical Sciences (T32AI0605357)

  • Maliheh Safari

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

Reviewing Editor

  1. Karla Kirkegaard, Stanford University School of Medicine, United States

Publication history

  1. Preprint posted: July 15, 2021 (view preprint)
  2. Received: July 26, 2021
  3. Accepted: April 19, 2022
  4. Accepted Manuscript published: May 5, 2022 (version 1)
  5. Version of Record published: May 19, 2022 (version 2)

Copyright

© 2022, Safari 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. Maliheh Safari
  2. Bhargavi Jayaraman
  3. Shumin Yang
  4. Cynthia Smith
  5. Jason D Fernandes
  6. Alan D Frankel
(2022)
Functional and structural segregation of overlapping helices in HIV-1
eLife 11:e72482.
https://doi.org/10.7554/eLife.72482
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