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Partners in kinesin activation

Kinesin-1 takes JIP1 (green) to axon tips, but not if FEZ1 (red) activity is blocked (bottom).

It takes two to turn on a kinesin, say Blasius et al. on page 11. Kinesin-1 motoring on microtubules requires cargo plus a second binding partner to relieve the motor of its inhibited conformation.

On its own, Kinesin-1 is an inactive motor. Inhibition of the solitary motor probably ensures that it is not needlessly burning ATP or clogging up the microtubule roadways when cargo-loaded motors need to get through.

Truncated versions of Kinesin-1 are more active than the full-length protein, suggesting that the deleted domains are autoinhibitory. Cargo binding is thought to activate Kinesin-1 by releasing inhibitory domains from the motor. One recently identified cargo is a scaffolding protein called JIP1, but the group now finds that binding of this cargo is not enough to activate Kinesin-1.

JIP1 binds to kinesin's light chain, but autoinhibition happens on the heavy chain, where the motor domain lies. The authors thus sought new binding partners for the heavy chain. A prominent partner from yeast two-hybrid assays was FEZ1—a mammalian homologue of a worm protein that supports neurite outgrowth.

Adding FEZ1 to the JIP1/Kinesin-1 mix jumpstarted motor activity. Exactly why a double whammy is needed for Kinesin-1 activation is not clear. Apparently, even a small amount of unwanted motor activity is dangerous enough to warrant a dual-layered prevention system.

In a second paper from the same group, Cai et al. (page 51) use FRET to uncover the conformational changes that accompany Kinesin-1 activation. FRET of the multiprotein mixture is technically difficult, so the group instead studied the active deletion mutants. They found two conformational differences between the structures of the full-length kinesin chains and the mutants.

In one expected change, the inhibitory C-terminal tail of the heavy chain moved away from the motor domain. This change is probably brought about by the binding of FEZ1. The second structural change moved the motor subunits of the two heavy chains closer together. The authors believe the closing of this gap—possibly upon the arrival of cargo—might be necessary for the motor to sit correctly on microtubules.

The authors are now testing whether FEZ1 is needed to move more Kinesin-1 cargoes. The next step will be to determine how FEZ1 binding to the motor is regulated.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 851K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Articles Social Bookmarking                            What's this?