Mechanism of IFT-A polymerization into trains for ciliary transport

Intraflagellar transport (IFT) is the highly conserved process by which proteins are transported along ciliary microtubules by a train-like polymeric assembly of IFT-A and IFT-B complexes. IFT-A is sandwiched between IFT-B and the ciliary membrane, consistent with its putative role in transporting transmembrane and membrane-associated cargoes. Here, we have used single-particle analysis electron cryomicroscopy (cryo-EM) to determine structures of native IFT-A complexes. We show that subcomplex rearrangements enable IFT-A to polymerize laterally on anterograde IFT trains, revealing a cooperative assembly mechanism. Surprisingly, we discover that binding of IFT-A to IFT-B shields the preferred lipid-binding interface from the ciliary membrane but orients an interconnected network of β-propeller domains with the capacity to accommodate diverse cargoes toward the ciliary membrane. This work provides a mechanistic basis for understanding IFT-train assembly and cargo interactions. [Display omitted] •Cryo-EM structures of native Leishmania tarentolae IFT-A complexes•Subcomplex rearrangements enable IFT-A to polymerize into lateral IFT trains•IFT-A has lipid specificity and can coat liposomes•Anterograde IFT-A positions cargo-binding β-propellers toward the ciliary membrane Structural analyses reveal how IFT-A, a highly conserved complex that transports transmembrane proteins within cilia, binds membranes and polymerizes into cargo-binding trains.