Karasmanis, E.P. orcid.org/0000-0002-0139-0210, Reimer, J.M., Kendrick, A.A. orcid.org/0000-0003-3254-4582 et al. (6 more authors) (2023) Lis1 relieves cytoplasmic dynein-1 autoinhibition by acting as a molecular wedge. Nature Structural & Molecular Biology, 30 (9). pp. 1357-1364. ISSN 1545-9993
Abstract
Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly. Lis1 is required for active dynein complexes to form, but how it enables this is unclear. Here, we present a structure of two yeast dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed ‘Chi,’ are required for Lis1’s regulation of dynein in Saccharomyces cerevisiae in vivo and the formation of active human dynein–dynactin–activating adapter complexes in vitro. We propose that this structure represents an intermediate in dynein’s activation pathway, revealing how Lis1 relieves dynein’s autoinhibited state.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2023. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Underpinning research; Normal biological development and functioning; Generic health relevance |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 20 Sep 2023 12:08 |
Last Modified: | 20 Sep 2023 12:09 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1038/s41594-023-01069-6 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:203509 |