1. Cell Biology
  2. Structural Biology and Molecular Biophysics

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
https://doi.org/10.7554/eLife.71229
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Cite this article
  1. John P Gillies
  2. Janice M Reimer
  3. Eva P Karasmanis
  4. Indrajit Lahiri
  5. Zaw Min Htet
  6. Andres E Leschziner
  7. Samara L Reck-Peterson
(2022)
Structural basis for cytoplasmic dynein-1 regulation by Lis1
eLife 11:e71229.
https://doi.org/10.7554/eLife.71229
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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.

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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  1. John P Gillies
  2. Janice M Reimer
  3. Eva P Karasmanis
  4. Indrajit Lahiri
  5. Zaw Min Htet
  6. Andres E Leschziner
  7. Samara L Reck-Peterson
(2022)
Structural basis for cytoplasmic dynein-1 regulation by Lis1
eLife 11:e71229.
https://doi.org/10.7554/eLife.71229

Share this article

https://doi.org/10.7554/eLife.71229

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    Structures of human dynein in complex with the lissencephaly 1 protein, LIS1

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    The lissencephaly 1 protein, LIS1, is mutated in type-1 lissencephaly and is a key regulator of cytoplasmic dynein-1. At a molecular level, current models propose that LIS1 activates dynein by relieving its autoinhibited form. Previously we reported a 3.1 Å structure of yeast dynein bound to Pac1, the yeast homologue of LIS1, which revealed the details of their interactions (Gillies et al., 2022). Based on this structure, we made mutations that disrupted these interactions and showed that they were required for dynein’s function in vivo in yeast. We also used our yeast dynein-Pac1 structure to design mutations in human dynein to probe the role of LIS1 in promoting the assembly of active dynein complexes. These mutations had relatively mild effects on dynein activation, suggesting that there may be differences in how dynein and Pac1/LIS1 interact between yeast and humans. Here, we report cryo-EM structures of human dynein-LIS1 complexes. Our new structures reveal the differences between the yeast and human systems, provide a blueprint to disrupt the human dynein-LIS1 interactions more accurately, and map type-1 lissencephaly disease mutations, as well as mutations in dynein linked to malformations of cortical development/intellectual disability, in the context of the dynein-LIS1 complex.

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