IFT-A structure reveals carriages for membrane protein transport into cilia
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Abstract
Intraflagellar transport (IFT) trains are massive molecular machines that traffic proteins between cilia and the cell body. Each IFT train is a dynamic polymer of two large complexes (IFT-A and -B) and motor proteins, posing a formidable challenge to mechanistic understanding. Here, we reconstituted the complete human IFT-A complex and obtained its structure using cryo-EM. Combined with AlphaFold prediction and genome-editing studies, our results illuminate how IFT-A polymerizes, interacts with IFT-B, and uses an array of β-propeller and TPR domains to create "carriages" of the IFT train that engage TULP adaptor proteins. We show that IFT-A⋅TULP carriages are essential for cilia localization of diverse membrane proteins, as well as ICK-the key kinase regulating IFT train turnaround. These data establish a structural link between IFT-A's distinct functions, provide a blueprint for IFT-A in the train, and shed light on how IFT evolved from a proto-coatomer ancestor.
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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
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391 · see citing works
Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., Yuan, D., Stroe, O., Wood, G., Laydon, A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkab1061 · Cited by 7,850 · see citing works
Protein complex prediction with AlphaFold-Multimer
Evans, R., O’Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., Žídek, A., Bates, R., Blackwell, S., Yim, J., et al. (2021) · doi:10.1101/2021.10.04.463034 · Cited by 3,808 · see citing works
Genes and molecular pathways underpinning ciliopathies
Reiter, J. F., & Leroux, M. R. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.60 · Cited by 1,588 · see citing works
The DHC1b (DHC2) Isoform of Cytoplasmic Dynein Is Required for Flagellar Assembly
Pazour, G. J., Dickert, B. L., & Witman, G. B. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.144.3.473 · Cited by 471 · see citing works
Mukhopadhyay, S., Wen, X., Chih, B., Nelson, C. D., Lane, W. S., Scales, S. J., & Jackson, P. K. (2010) · Genes & Development · doi:10.1101/gad.1966210 · Cited by 435 · see citing works
The Intraflagellar Transport Machinery
Taschner, M., & Lorentzen, E. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028092 · Cited by 349 · see citing works
Cytoplasmic Dynein Heavy Chain 1b Is Required for Flagellar Assembly in<i>Chlamydomonas</i>
Porter, M. E., Bower, R., Knott, J. A., Byrd, P., & Dentler, W. (1999) · Molecular Biology of the Cell · doi:10.1091/mbc.10.3.693 · Cited by 333 · see citing works
BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone
Ye, F., Nager, A. R., & Nachury, M. V. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709041 · Cited by 256 · see citing works
The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking
Liem, K. F., Ashe, A., He, M., Satir, P., Moran, J., Beier, D., Wicking, C., & Anderson, K. V. (2012) · Journal of Cell Biology · doi:10.1083/jcb.201110049 · Cited by 214 · see citing works
Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins
Badgandi, H. B., Hwang, S.-H., Shimada, I. S., Loriot, E., & Mukhopadhyay, S. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201607095 · Cited by 182 · see citing works
Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways
Sigg, M. A., Menchen, T., Lee, C., Johnson, J., Jungnickel, M. K., Choksi, S. P., Garcia, G., Busengdal, H., Dougherty, G. W., Pennekamp, P., et al. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.11.014 · Cited by 130 · see citing works
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Primary cilia as dynamic and diverse signalling hubs in development and disease
Mill, P., Christensen, S. T., & Pedersen, L. B. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00587-9 · Cited by 417 · see citing works
Primary cilia-mediated regulation of microglial secretion in Alzheimer’s disease
Yeo, S., Jang, J., Jung, H. J., Lee, H., & Choe, Y. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1250335 · Cited by 18 · see citing works
Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis
Huang, A. S., Li, A. S. M., & Hor, C. H. H. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1650884 · Cited by 4 · see citing works
- Authors
- Hesketh, S. J., Mukhopadhyay, A. G., Nakamura, D., Toropova, K., & Roberts, A. J.
- Affiliations
- Institute of Structural and Molecular Biology (GB)
- Corresponding author
- Toropova, Katerina
- Roberts, Anthony J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 185
- Issue
- 26
- Pages
- 4971-4985.e16
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W4310668128
- Cited by
- 83
- References
- 13
- Citations by year
- 2026: 10 · 2025: 29 · 2024: 22 · 2023: 16 · 2022: 6
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (202679/Z/16/Z, Z/17/Z, 202679, 206166/Z/17/Z, 206166, 217186/Z/19/Z)
- University of Bristol
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BB/S007202/1)
- 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
- intraflagellar transport, IFT-A complex, IFT-B complex, cilia, membrane protein transport, beta-propeller domain, TPR domain, cryo-EM structure
- MeSH terms
- Biological Transport, Cilia, Dyneins, Flagella, Humans, Membrane Proteins, Kinesins, Protein Transport
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