Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements
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Cilia are multifunctional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multimotor assemblies with kinesin-II. Combining these data with insights from single-particle EM, we discover that dynein-2 dimers are intrinsically autoinhibited. Inhibition is mediated by trapping dynein-2's mechanical 'linker' and 'stalk' domains within a novel motor-motor interface. We find that linker-mediated inhibition enables efficient transport of dynein-2 by kinesin-II in vitro. These results suggest a conserved mechanism for autoregulation among dimeric dyneins, which is exploited as a switch for dynein-2's recycling activity during IFT.
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Progress has been made in understanding interactions between specific IFT particle polypeptides and specific ciliary cargo proteins or motor subunits during anterograde or retrograde IFT, as well as how IFT motor activity is regulated.
“Likewise, progress has been made towards understanding the interactions between specific IFT particle polypeptides and specific ciliary cargo proteins or motor subunits during anterograde or retrograde IFT, as well as how IFT motor activity is regulated 24, 48–52.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [49]
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- Authors
- Toropova, K., Mladenov, M., & Roberts, A. J.
- Affiliations
- Institute of Structural and Molecular Biology (GB)
- Corresponding author
- Roberts, Anthony J
- Venue
- Nature Structural & Molecular Biology
- Published
- 2017-04-10
- Volume
- 24
- Issue
- 5
- Pages
- 461-468
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC5420313
- OpenAlex
- W2607056421
- Cited by
- 85
- References
- 80
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 7 · 2020: 16 · 2019: 12 · 2018: 9 · 2017: 6
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- BIROn (Birkbeck, University of London) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (104196/Z/14/Z)
- Biotechnology and Biological Sciences Research Council (BB/P008348/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- retrograde intraflagellar transport, cilia, autoinhibition, stalk domain, kinesin-2, mechanochemistry
- MeSH terms
- Dyneins, Humans, Microscopy, Electron, Models, Biological, Models, Molecular, Protein Conformation, Kinesins, Protein Multimerization
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