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

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 angstrom. 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.

Automated summary

This study reports the cryo-EM structures of human IFT-A complexes, revealing their lariat shape and vital zinc-binding domains. The cargo adapter TULP3 interacts with IFT-A through its N-terminal region, and mutations disrupt cargo transport. These findings provide insights into the structure and function of IFT-A, ciliary transport, and disease mutations.