Structural basis for cytoplasmic dynein-1 regulation by Lis1

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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

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John P Gillies

Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States

Competing interests
No competing interests declared.
Janice M Reimer

Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States

Competing interests
No competing interests declared.
Eva P Karasmanis

Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States

Competing interests
No competing interests declared.
Indrajit Lahiri

Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India

Competing interests
No competing interests declared.
Zaw Min Htet

Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States

Competing interests
No competing interests declared.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-7732-7023
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.

"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.

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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.