Molecular basis for the activation of outer dynein arms in cilia
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Abstract
Multiciliogenesis requires large-scale biosynthesis of motility-powering axonemal inner and outer dynein arm motors (IDAs and ODAs) before their intraflagellar transport (IFT) into cilia. ODAs are inhibited by the packaging chaperone Shulin during ciliogenesis in Tetrahymena thermophila . How Shulin is released for ODAs to become active inside cilia remains unclear. Here we uncover a molecular mechanism for ODA activation. We establish interactions between DNAAF9 (human Shulin) and mammalian ODA subunits, IFT proteins and the ciliary small guanosine triphosphatase (GTPase) ARL3 using proteomics and in vitro reconstitutions. Mutagenesis combined with biochemical and structural studies reveal that DNAAF9 and Shulin preferentially bind active Arl3–GTP highlighting a cross-species conservation of this interaction. GTP-loaded Arl3 can access, bind and displace Shulin from the packaged ODA–Shulin complex. We propose that, once the inhibited ODA complex enters growing cilia, Arl3–GTP displaces Shulin (DNAAF9) and sequesters it away from ODAs, promoting activation of their motility specifically inside cilia.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · cited 1× · see citing works
“Full-length DNAAF9 and ARL3 sequences were used to predict an interaction between the two in the presence of one molecule of GTP or GDP using the default parameters 19 .”
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A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia
Lange, S. M., Bennett, J. A., Eisert, R. J., & Brown, A. (2025) · Cell · doi:10.1016/j.cell.2025.07.043 · Cited by 11 · see citing works
- Authors
- Issa, K. H. B., Ren, M., Burnet, B., Lu, H., Melia, C., Heesom, K., Roberts, A. J., Roy, S., & Mali, G. R.
- Affiliations
- University of Oxford (GB)
- University of Bristol (GB)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Mali, Girish R.
- Venue
- Nature Structural & Molecular Biology
- Published
- 2025-09-29
- Volume
- 32
- Issue
- 12
- Pages
- 2454-2464
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC12700831
- OpenAlex
- W4414589064
- Cited by
- 6
- References
- 2
- Citations by year
- 2026: 3 · 2025: 3
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Explore Bristol Research (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- Academy of Medical Sciences (SBF007\1001)
- Medical Research Council (MR/X007219/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- outer dynein arm, cilia, ciliogenesis, intraflagellar transport, axoneme, Tetrahymena thermophila, GTP binding, ciliary motility
- MeSH terms
- Animals, Cilia, Dyneins, Guanosine Triphosphate, Humans, Models, Molecular, Protein Binding, Tetrahymena thermophila, Molecular Chaperones, ADP-Ribosylation Factors
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