The correct localization of Hedgehog effectors to the tip of primary cilia is critical for proper signal transduction. The conserved non-motile kinesin Kif7 defines a "cilium-tip compartment" by localizing to the distal ends of axonemal microtubules. How Kif7 recognizes microtubule ends remains unknown. We find that Kif7 preferentially binds GTP-tubulin at microtubule ends over GDP-tubulin in the mature microtubule lattice, and ATP hydrolysis by Kif7 enhances this discrimination. Cryo-electron microscopy (cryo-EM) structures suggest that a rotated microtubule footprint and conformational changes in the ATP-binding pocket underlie Kif7's atypical microtubule-binding properties. Finally, Kif7 not only recognizes but also stabilizes a GTP-form of tubulin to promote its own microtubule-end localization. Thus, unlike the characteristic microtubule-regulated ATPase activity of kinesins, Kif7 modulates the tubulin mechanochemical cycle. We propose that the ubiquitous kinesin fold has been repurposed in Kif7 to facilitate organization of a spatially restricted platform for localization of Hedgehog effectors at the cilium tip.
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| http://dx.doi.org/10.1016/j.devcel.2019.04.001 | DOI Listing |
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Article Synopsis
- Kinesin motors primarily move toward the plus end of microtubules, but the reason for this directionality is not well understood.
- To investigate this, the researchers modeled kinesin-1 and its interactions with microtubules, revealing that kinesin-1 binding leads to structural changes in microtubules that promote binding and movement.
- Their findings provide insights into how kinesin's stepping direction is established and how microtubules influence kinesin's function during its catalytic cycle.
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