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

Lacey, Samuel E; Foster, Helen; Pigino, Gaia

doi:10.1038/s41594-022-00905-5

Cited by 54 publications

(75 citation statements)

References 58 publications

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“…Electron densities for the HN domains of COMMD9 and COMMD10 were weak, and no clear densities were seen for the HN domains of COMMD5 or COMMD7 presumably due to flexibility. Notably, the structure closely matches the complex predicted by AlphaFold2 multimer (59, 68) for the four proteins ( Fig. S3E ).…”

Section: Resultssupporting

confidence: 70%

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Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Collins

McConville

Palmer

et al. 2023

Preprint

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The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed of VPS35L, VPS26C and VPS29, and the CCC complex which contains ten subunits COMMD1-COMMD10 and two coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy and in silico predictions we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilised by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a sixteenth subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

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Section: Resultssupporting

confidence: 70%

“…Notably, the structure closely matches the complex predicted by AlphaFold2 multimer (59,68) for the four proteins (Fig. S3E).…”

Section: The Commd Proteins Assemble Into Distinct Heteromeric Complexessupporting

confidence: 69%

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Collins

McConville

Palmer

et al. 2023

Preprint

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“…These insights allow us to determine the molecular impacts of disease mutations on complex formation and ciliary trafficking. 37,40,52 and provided valuable information for IFT-A assembly. However, the resulting models seem to be different from each other and from our structures (Supplementary information, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although our structural observation is mostly consistent with the previous molecular analyses based on biochemical and genetic data, 16,19,44,47 it shows significant differences from the recent cryo-ET-based integrative structural models (discussed below). 40,52 IFT-A-TULP3 complex structure and insights into cargo transport We determined the cryo-EM structure of IFT-A in complex with TULP3 to gain insights into ciliary transport. TULP3 is an adapter protein that mediates the interaction between IFT-A and membrane-embedded or -associated cargos.…”

Section: Organization Of the Ift-a Complexmentioning

confidence: 99%

Human IFT-A complex structures provide molecular insights into ciliary transport

Jiang,

Palicharla,

Miller

et al. 2023

Cell Res

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Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0–3.9 Å. IFT-A adopts a “lariat” shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.

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“…We note that the structure of the IFT-A complex has also been recently worked out in other ciliated organisms [7][8][9] . Although not highlighted here, these studies provide additional important insights into the assembly and mode of operation of this intriguing complex.…”

mentioning

confidence: 63%

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

Cited by 54 publications

References 58 publications

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Human IFT-A complex structures provide molecular insights into ciliary transport

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

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