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Cited by 23Microtubule and mitosis dynamicsGenetic and Kidney Cyst DiseasesEnzyme Structure and Function

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

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Reimer, Janice M, DeSantis, Morgan E, Reck-Peterson, Samara L, Leschziner, Andres E·2023·eLife
DOI 10.7554/elife.84302PMC PMC9889085

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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 3.1 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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Metadata

Authors
Reimer, J. M., DeSantis, M. E., Reck-Peterson, S. L., & Leschziner, A. E.
Affiliations
  • University of California San Diego (US)
  • University of Michigan (US)
  • Department of Cellular and Molecular Medicine, University of California, San Diego
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2023-01-24
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.84302
PMC
PMC9889085
OpenAlex
W4317869419
Cited by
23
References
1
Citations by year
2026: 5 · 2025: 6 · 2024: 3 · 2023: 7
FWCI
3.04
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Damon Runyon Cancer Research Foundation (DRG-2370-19)
  • Jane Coffin Childs Memorial Fund for Medical Research
  • Howard Hughes Medical Institute
  • National Institute of General Medical Sciences (R35 GM141825, R01 GM107214, R35 GM145296)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
LIS1, cytoplasmic dynein-1, PAC1, dynein activation, malformations of cortical development, intellectual disability, cryo-EM structure, pathogenic variants
MeSH terms
Dyneins, Endoribonucleases, Humans, Microtubule-Associated Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Classical Lissencephalies and Subcortical Band Heterotopias

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