The structural basis of intraflagellar transport at a glance

Abstract

The intraflagellar transport (IFT) system is a remarkable molecular machine used by cells to assemble and maintain the cilium, a long organelle extending from eukaryotic cells that gives rise to motility, sensing and signaling. IFT plays a critical role in building the cilium by shuttling structural components and signaling receptors between the ciliary base and tip. To provide effective transport, IFT-A and IFT-B adaptor protein complexes assemble into highly repetitive polymers, called IFT trains, that are powered by the motors kinesin-2 and IFT-dynein to move bidirectionally along the microtubules. This dynamic system must be precisely regulated to shuttle different cargo proteins between the ciliary tip and base. In this Cell Science at a Glance article and the accompanying poster, we discuss the current structural and mechanistic understanding of IFT trains and how they function as macromolecular machines to assemble the structure of the cilium.

Combinations of deletion and missense variations of the dynein-2 DYNC2LI1 subunit found in skeletal ciliopathies cause ciliary defects

“…To achieve its function as a retrograde motor for the IFT machinery, the dynein-2 complex must be transported to the ciliary tip as an anterograde IFT cargo. The cryo-EM structure of the human dynein-2 complex, in conjunction with the cryoelectron tomographic structure of Chlamydomonas anterograde IFT trains, suggested that the dynein-2 complex and the IFT-B complex interact with each other via multiple sites 17 , 22 – 24 . In addition, a study using Chlamydomonas demonstrated that the IFT-B subunit IFT54 directly binds to IFT dynein via its LIC subunit 25 .…”

“…Our model is largely consistent with the recently clarified cryo-EM structure of the human dynein-2 complex 22 , in which two molecules of DYNC2H1 adopt asymmetric conformations in the tail region, with each DYNC2H1 molecule binding to DYNC2LI1, and either WDR60 or WDR34. Docking of the dynein-2 structure into the anterograde IFT train structure of Chlamydomonas flagella 23 clarified by cryoelectron tomography suggested that each dynein-2 complex spans out multiple IFT-B repeats when it is transported as a cargo of the anterograde IFT train 17 , 22 , 24 . In agreement with the docking model, interactome analyses of WDR60 and WDR34 suggested that dynein-2 interacts with multiple IFT-B subunits 21 .…”

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

“…29 These range from proteins involved in intraflagellar transport (IFT), anterograde and retrograde transport systems required to generate the cilium, transport proteins along its length, and for appropriate signaling; transition zone proteins that form a barrier regulating the protein composition of the cilium; and cargo adaptor proteins. 28,30,31 The cystic kidney disease associated with these syndromic PKD ciliopathies may be due to reduced polycystin-complex (and/or FPC) in the cilium, [32][33][34] analogous to the ER proteostasis defects causing ADPKD/ADPLD. However, the finding from in vivo studies that cilia removal in the kidney in the context of PC1 loss partially rescues PC1-associated cystic disease questions whether there are additional ciliary factors causing or preventing PKD.…”

Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme

“…On the other hand, IFT complex B participates in the anterograde transport and it is essential for the assembly and maintenance of cilia. To avoid collision, IFT-A use the A-tubule, and IFT-B move along the B-tubule (36)(37)(38)(39).…”