Allosteric inhibition of kinesin-5 modulates its processive directional motility

Kwok, Benjamin H.; Kapitein, Lukas C.; Kim, Jeffrey H.; Peterman, Erwin J. G.; Schmidt, Christoph F.; Kapoor, Tarun M.

doi:10.1038/nchembio812

Cited by 107 publications

(146 citation statements)

References 28 publications

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“…The motility of kinesins can be modulated at several levels. For example, the processivity of these motors, and hence their speed, may be reduced by interference with the properties of the kinesin itself, such as ATP binding and hydrolysis or allosteric inhibition of directional movement (39,40). Also, posttranslational modifications of the microtubules on which the kinesins walk have been reported to affect the motility of kinesins (41).…”

Section: Discussionmentioning

confidence: 99%

Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans

Burghoorn¹,

Dekkers²,

Rademakers³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

116

178

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In the cilia of the nematode Caenorhabditis elegans, anterograde intraflagellar transport (IFT) is mediated by two kinesin-2 complexes, kinesin II and OSM-3 kinesin. These complexes function together in the cilia middle segments, whereas OSM-3 alone mediates transport in the distal segments. Not much is known about the mechanisms that compartmentalize the kinesin-2 complexes or how transport by both kinesins is coordinated. Here, we identify DYF-5, a conserved MAP kinase that plays a role in these processes. Fluorescence microscopy and EM revealed that the cilia of dyf-5 loss-of-function (lf) animals are elongated and are not properly aligned into the amphid channel. Some cilia do enter the amphid channel, but the distal ends of these cilia show accumulation of proteins. Consistent with these observations, we found that six IFT proteins accumulate in the cilia of dyf-5(lf) mutants. In addition, using genetic analyses and live imaging to measure the motility of IFT proteins, we show that dyf-5 is required to restrict kinesin II to the cilia middle segments. Finally, we show that, in dyf-5(lf) mutants, OSM-3 moves at a reduced speed and is not attached to IFT particles. We propose that DYF-5 plays a role in the undocking of kinesin II from IFT particles and in the docking of OSM-3 onto IFT particles.cilia length ͉ dyf-5 ͉ intraflagellar transport C ilia are present on almost every vertebrate cell and have important functions in motility or sensation. Within cilia, structural components and signaling molecules are transported by a specialized system, called intraflagellar transport (IFT) (1-5). Transport from the base of the cilia to the tip (anterograde) is mediated by kinesin-2 motor complexes, whereas dynein motor complexes mediate transport back to the base (retrograde). The nematode Caenorhabditis elegans has 60 ciliated neurons, including eight pairs of amphid neurons exposed to the environment (6). The cilia of these neurons can be divided into a middle segment with nine doublet microtubules and a distal segment with nine singlet microtubules (7). In the middle segments, two distinct kinesin-2 motor complexes mediate anterograde transport, heterotrimeric kinesin II, encoded by klp-11, klp-20, and kap-1 and homodimeric OSM-3 kinesin (8). In the distal segments, transport is mediated by only OSM-3 (8). Live imaging of the movement of these kinesins suggests that kinesin II alone moves at 0.5 m/s, and OSM-3 alone moves at 1.3 m/s, whereas the two motor complexes together move at 0.7 m/s (8). Recently, Pan et al. (9) have shown that these in vivo transport rates can be reconstituted in vitro by using purified kinesin II and OSM-3 motors. Thus far, two proteins have been identified that are required to stabilize IFT complexes transported by both kinesin II and OSM-3, BBS-7 and BBS-8 (10). However, it remains unclear how kinesin II is restricted to the cilia middle segments, whereas OSM-3 is allowed to enter the distal segments and what the functional significance is of this compartmentalization.Recently, Evans e...

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Section: Discussionmentioning

confidence: 99%

Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans

Burghoorn¹,

Dekkers²,

Rademakers³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

116

178

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“…nm at ~35 nm per second, towards the plus-end of the microtubule 59 . Experiments in X. laevis extracts show that the rate of spindle assembly is limited by this rate of KIF11-driven microtubule sliding 60 .…”

Section: Centrosome Separationmentioning

confidence: 99%

Prime movers: the mechanochemistry of mitotic kinesins

Cross

McAinsh

2014

Nat Rev Mol Cell Biol

188

203

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“…Force-insensitive velocities may allow Eg5 to move under considerable tension while short run lengths prevent interference among neighboring motors. Recent singlemolecule fluorescence imaging of GFP-labeled Eg5 tetramers indicates that, in addition to ATP-driven stepping, tetramers also undergo biased diffusion toward the microtubule plusend, raising the possibility of unique modes of motion in vivo [55]. Extending kinetic and mechanical measurements to Eg5 tetramers, while technically difficult, will be critical to fully understand Eg5 regulation and motility in spindles.…”

Section: Eg5 Processivity: the Challenge Awaitsmentioning

confidence: 99%

To step or not to step? How biochemistry and mechanics influence processivity in Kinesin and Eg5

Valentine

Gilbert

2007

Current Opinion in Cell Biology

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Conventional kinesin and Eg5 are essential nanoscale motor proteins. Single-molecule and presteady-state kinetic experiments indicate that both motors use similar strategies to generate movement along microtubules, despite having distinctly different in vivo functions. Single molecules of kinesin, a long-distance cargo transporter, are highly processive, binding the microtubule and taking 100 or more sequential steps at velocities of up to 700 nm/s before dissociating, whereas Eg5, a motor active in mitotic spindle assembly, is also processive, but takes fewer steps at a slower rate. By dissecting the structural, biochemical and mechanical features of these proteins, we hope to learn how kinesin and Eg5 are optimized for their specific biological tasks, while gaining insight into how biochemical energy is converted into mechanical work.

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Allosteric inhibition of kinesin-5 modulates its processive directional motility

Cited by 107 publications

References 28 publications

Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans

Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans

Prime movers: the mechanochemistry of mitotic kinesins

To step or not to step? How biochemistry and mechanics influence processivity in Kinesin and Eg5

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