1. Cell Biology
  2. Structural Biology and Molecular Biophysics

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

  1. Janice M Reimer
  2. Morgan E DeSantis
  3. Samara L Reck-Peterson  Is a corresponding author
  4. Andres E Leschziner  Is a corresponding author
  1. University of California, San Diego, United States
  2. University of Michigan-Ann Arbor, United States
https://doi.org/10.7554/eLife.84302
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  1. Janice M Reimer
  2. Morgan E DeSantis
  3. Samara L Reck-Peterson
  4. Andres E Leschziner
(2023)
Structures of human dynein in complex with the lissencephaly 1 protein, LIS1
eLife 12:e84302.
https://doi.org/10.7554/eLife.84302
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Abstract

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 3.1Å 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 interaction 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.

Data availability

Cryo-EM maps and resulting models have been deposited in the EM Data Bank (maps) and PDB (models). Raw micrographs have been deposited in EMPIAR. Accession numbers are listed in Supplementary File 1.

The following data sets were generated

Article and author information

Author details

  1. Janice M Reimer

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Morgan E DeSantis

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4096-8548

  3. 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
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1553-465X

  4. 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
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7732-7023

Funding

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

  • Janice M Reimer

Jane Coffin Childs Memorial Fund for Medical Research

  • Morgan E DeSantis

Howard Hughes Medical Institute

  • Samara L Reck-Peterson

National Institute of General Medical Sciences (R35 GM141825)

  • Samara L Reck-Peterson

National Institute of General Medical Sciences (R01 GM107214)

  • Andres E Leschziner

National Institute of General Medical Sciences (R35 GM145296)

  • Andres E Leschziner

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

Reviewing Editor

  1. Anna Akhmanova, Utrecht University, Netherlands

Version history

  1. Preprint posted: October 8, 2022 (view preprint)
  2. Received: October 21, 2022
  3. Accepted: January 8, 2023
  4. Accepted Manuscript published: January 24, 2023 (version 1)
  5. Version of Record published: January 31, 2023 (version 2)

Copyright

© 2023, Reimer 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. Janice M Reimer
  2. Morgan E DeSantis
  3. Samara L Reck-Peterson
  4. Andres E Leschziner
(2023)
Structures of human dynein in complex with the lissencephaly 1 protein, LIS1
eLife 12:e84302.
https://doi.org/10.7554/eLife.84302

Share this article

https://doi.org/10.7554/eLife.84302

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Further reading

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    Structural basis for cytoplasmic dynein-1 regulation by Lis1

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    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 3.1 Å 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.

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