IFT-A structure reveals carriages for membrane protein transport into cilia

Hesketh, Sophie J.; Mukhopadhyay, Aakash Gautam; Nakamura, Dai; Toropova, Katerina; Roberts, A. J.

doi:10.1016/j.cell.2022.11.010

Cited by 47 publications

(42 citation statements)

References 106 publications

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“…These interactions occur across the interface between adjacent repeats, meaning that they are unlikely to be detected after purification for coimmunoprecipitation assays. This is consistent with data showing that purified IFT-A and IFT-B complexes do not oligomerize, even at high concentrations 11,37 . This leads to a conundrum of how the IFT-B polymer is assembled when the interactions forming lateral repeats are too weak to be detected biochemically.…”

Section: Discussionsupporting

confidence: 92%

“…5). Subsequently released results from a single-particle structure of isolated IFT-A complexes 37 and crosslinking mass spectrometry of purified IFT-B 38 are both consistent with our model.…”

Section: Discussionsupporting

confidence: 84%

“…This unknown component could therefore be responsible for starting the process of fixing mobile domains into a single conformation during polymerization. Finally, the connection between IFT-A and IFT-B had recently been shown to be mediated by an interaction between the C terminus of IFT88 in IFT-B1 and the C terminus of IFT144 in IFT-A 37,40 . These two elements are close enough in our model to interact, although we do not have the resolution in this region to detect the contact.…”

Section: Discussionmentioning

confidence: 99%

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The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains

Lacey

Foster

Pigino

2023

Nat Struct Mol Biol

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Anterograde intraflagellar transport (IFT) trains are essential for cilia assembly and maintenance. These trains are formed of 22 IFT-A and IFT-B proteins that link structural and signaling cargos to microtubule motors for import into cilia. It remains unknown how the IFT-A/-B proteins are arranged into complexes and how these complexes polymerize into functional trains. Here we use in situ cryo-electron tomography of Chlamydomonas reinhardtii cilia and AlphaFold2 protein structure predictions to generate a molecular model of the entire anterograde train. We show how the conformations of both IFT-A and IFT-B are dependent on lateral interactions with neighboring repeats, suggesting that polymerization is required to cooperatively stabilize the complexes. Following three-dimensional classification, we reveal how IFT-B extends two flexible tethers to maintain a connection with IFT-A that can withstand the mechanical stresses present in actively beating cilia. Overall, our findings provide a framework for understanding the fundamental processes that govern cilia assembly.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains

Lacey

Foster

Pigino

2023

Nat Struct Mol Biol

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“…In agreement with the importance of this distinctive domain in IFT-A assembly, the authors found that mutating key interface residues in the IFT140 TPR almost completely disrupts its binding to IFT144. Moreover, expressing this IFT140 mutant in IMCD3 cells fails to rescue the cilium assembly defects associated with the loss of IFT140, underlining the functional relevance of this interaction 3 .…”

mentioning

confidence: 97%

“…Conversely, the non-core IFT-A subunits, IFT121, IFT139 and IFT43, together with the N-terminal half of IFT122, actually constitute the most rigid module of this protein complex. With this new structural organization in mind, the authors renamed these modules as IFT-A1 and IFT-A2, respectively 3 .…”

mentioning

confidence: 99%

Building train carriages for ciliary transport: (IFT-)A complex task

Goncalves-Santos

De-Castro

et al. 2023

Commun Biol

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Cilia assembly and function require intraflagellar transport (IFT), a mechanism that uses “trains” to transport cargoes into and out of cilia. While much has been learned about IFT in the past decades, IFT train assembly, loading of cargo and transport regulation have remained poorly understood. In a recent study, Hesketh, Mukhopadhyay and colleagues obtained the complete structure of the IFT-A complex, a key element of IFT trains. By modelling IFT-A into anterograde trains and performing structure-guided mutagenesis, the authors uncover how the IFT-A complex polymerizes and forms carriages to accomplish its distinctive functions.

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Architecture of RabL2‐associated complexes at the ciliary base: A structural modeling perspective

Boegholm,

Petriman,

Tanvir

et al. 2024

BioEssays

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Cilia are slender, micrometer‐long organelles present on the surface of eukaryotic cells. They function in signaling and locomotion and are constructed by intraflagellar transport (IFT). The assembly of IFT complexes into so‐called IFT trains to initiate ciliary entry at the base of the cilium remains a matter of debate. Here, we use structural modeling to provide an architectural framework for how RabL2 is anchored at the ciliary base via CEP19 before being handed over to IFT trains for ciliary entry. Our models suggest that the N‐terminal domain of CEP43 forms a homo‐dimer to anchor at the subdistal appendages of cilia through a direct interaction with CEP350. A long linker region separates the N‐terminal domain of CEP43 from the C‐terminal domain, which captures CEP19 above the subdistal appendages and close to the distal appendages. Furthermore, we present a structural model for how RabL2‐CEP19 associates with the IFT‐B complex, providing insight into how RabL2 is handed over from CEP19 to the IFT complex. Interestingly, RabL2 association with the IFT‐B complex appears to induce a significant conformational change in the IFT complex via a kink in the coiled‐coils of the IFT81/74 proteins, which may prime the IFT machinery for entry into cilia.

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IFT-A structure reveals carriages for membrane protein transport into cilia

Cited by 47 publications

References 106 publications

The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains

The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains

Building train carriages for ciliary transport: (IFT-)A complex task

Architecture of RabL2‐associated complexes at the ciliary base: A structural modeling perspective

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