Kinesin, 30 years later: Recent insights from structural studies

Abstract

Motile kinesins are motor proteins that move unidirectionally along microtubules as they hydrolyze ATP. They share a conserved motor domain (head) which harbors both the ATP-and microtubule-binding activities. The kinesin that has been studied most moves toward the microtubule (1)-end by alternately advancing its two heads along a single protofilament. This kinesin is the subject of this review. Its movement is associated to alternate conformations of a peptide, the neck linker, at the C-terminal end of the motor domain. Recent progress in the understanding of its structural mechanism has been made possible by high-resolution studies, by cryo electron microscopy and X-ray crystallography, of complexes of the motor domain with its track protein, tubulin. These studies clarified the structural changes that occur as ATP binds to a nucleotide-free microtubule-bound kinesin, initiating each mechanical step. As ATP binds to a head, it triggers orientation changes in three rigid motor subdomains, leading the neck linker to dock onto the motor core, which directs the other head toward the microtubule (1)-end. The relationship between neck linker docking and the orientations of the motor subdomains also accounts for kinesin's processivity, which is remarkable as this motor protein only falls off from a microtubule after taking about a hundred steps. As tools are now available to determine high-resolution structures of motor domains complexed to their track protein, it should become possible to extend these studies to other kinesins and relate their sequence variations to their diverse properties.

Regulation of Axonal Transport by Protein Kinases

“…The amino terminal globular heads of KIF5 form the motor domains and contain ATP and microtubule-binding sites. Kinesin-1 is able to take steps along the microtubule by alternately detaching and advancing each of its two globular heads [104]. High-resolution X-ray crystallography and cryo-electron microscopy of kinesin-1 in complex with tubulin in both ATP-bound and nucleotide-free states have provided insights into how the motor moves [104].…”

“…Kinesin-1 is able to take steps along the microtubule by alternately detaching and advancing each of its two globular heads [104]. High-resolution X-ray crystallography and cryo-electron microscopy of kinesin-1 in complex with tubulin in both ATP-bound and nucleotide-free states have provided insights into how the motor moves [104]. ATP binding to the 'front' motor domain not only allows high-affinity binding to microtubules but also triggers conformational changes in the 'rear' globular head that allows it to detach from microtubules and take a step.…”

Kinesin-2 motors: Kinetics and biophysics

“…These experiments are technically challenging and depend on ATP analogs and neck linker insertions to specifically affect the duration of the one-head bound state but not the two-head-bound state. Moreover, it is difficult to reconcile this new model with high resolution X-ray crystallography and cryo-electron microscopy studies (27,102). These structures indicate that ATP binding induces a large structural change within the catalytic motor domain that drives docking of the neck linker and therefore immediately results in a forward step.…”

KIFC1: a promising chemotherapy target for cancer treatment?

“…Kinesins including KIFC1 bind to microtubules with their motor domains, and ATP hydrolysis sites [103] included by these motor domains are popular disturbing sites for designed drugs. As KIFC1 has emerged popular as a chemotherapy target, three small-molecule inhibitors of KIFC1 have been thus far highlighted.…”