1. Cell Biology
  2. Structural Biology and Molecular Biophysics
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Structural basis for cytoplasmic dynein-1 regulation by Lis1

  1. John P Gillies
  2. Janice M Reimer
  3. Eva P Karasmanis
  4. Indrajit Lahiri
  5. Zaw Min Htet
  6. Andres E Leschziner  Is a corresponding author
  7. Samara L Reck-Peterson  Is a corresponding author
  1. University of California, San Diego, United States
  2. Indian Institute of Science Education and Research Mohali, India
Research Article
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Cite this article as: eLife 2022;11:e71229 doi: 10.7554/eLife.71229

Abstract

The lissencephaly 1 gene, LIS1, is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein–Lis1 complex. Our 3.1Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's ß-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function.

Data availability

The Cryo-EM map and model of the dynein-Lis1 complex have been deposited in the EMDB (23829) and the PDB (7MGM).

Article and author information

Author details

  1. John P Gillies

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  2. Janice M Reimer

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  3. Eva P Karasmanis

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  4. Indrajit Lahiri

    Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
    Competing interests
    No competing interests declared.
  5. Zaw Min Htet

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  6. Andres E Leschziner

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    For correspondence
    aleschziner@ucsd.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7732-7023
  7. Samara L Reck-Peterson

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    For correspondence
    sreckpeterson@ucsd.edu
    Competing interests
    Samara L Reck-Peterson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1553-465X

Funding

Howard Hughes Medical Institute

  • Samara L Reck-Peterson

National Institutes of Health (R35 GM141825)

  • Samara L Reck-Peterson

National Institutes of Health (R01 GM107214)

  • Andres E Leschziner

Damon Runyon Cancer Research Foundation (DRG-2370-19)

  • Janice M Reimer

National Institutes of Health (T32 GM008326)

  • John P Gillies

Jane Coffin Childs Memorial Fund for Medical Research

  • Eva P Karasmanis

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

Reviewing Editor

  1. Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: June 12, 2021
  2. Accepted: January 6, 2022
  3. Accepted Manuscript published: January 7, 2022 (version 1)

Copyright

© 2022, Gillies 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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