Common general anesthetic propofol impairs kinesin processivity

Bensel, Brandon M.; Guzik-Lendrum, Stephanie; Masucci, Erin M; Woll, Kellie A.; Eckenhoff, Roderic G.; Gilbert, Susan P.

doi:10.1073/pnas.1701482114

Cited by 26 publications

(53 citation statements)

References 71 publications

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“…It seems likely that these inhibitors will work in a similar way and recognize specific sequences in this region of the particular motor. A recent study of inhibition of kinesin-1 by the general anesthetic propofol showed that kinesins active in interphase are also susceptible to perturbation of their ATPase cycles by small-molecule binding; this could be explained through mechanisms related to disruption of subdomain rearrangements ( 68 ). Thus, our study of BTB-1 inhibition of Kif18A reinforces a common mechanism of allosteric kinesin inhibition through binding at the dynamic interface of subdomains within the kinesin motor domain, either on or off the MT ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of human kinesin-8 function and inhibition

Locke

Joseph

Peña

et al. 2017

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

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SignificanceKinesins are a superfamily of ATP-dependent motors important for many microtubule-based functions, including multiple roles in mitosis. Small-molecule inhibitors of mitotic kinesins disrupt cell division and are being developed as antimitotic therapies. We investigated the molecular mechanism of the multitasking human mitotic kinesin Kif18A and its inhibition by the small molecule BTB-1. We used cryo-electron microscopy to visualize nucleotide-dependent conformational changes in microtubule-bound Kif18A, and the conformation of microtubule-bound, BTB-1-bound Kif18A. We calculated a putative BTB-1–binding site and validated this site experimentally to reveal the BTB-1 inhibition mechanism. Our work points to a general mechanism of kinesin inhibition, with wide implications for a targeted blockade of these motors in both dividing and interphase cells.

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Section: Discussionmentioning

confidence: 99%

Structural basis of human kinesin-8 function and inhibition

Locke

Joseph

Peña

et al. 2017

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

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“…Previously, we reported that the commonly administered general anesthetic propofol ( Fig. 2 A ) at clinically relevant concentrations inhibits the processive movement of kinesin-1 KIF5B and kinesin-2 KIF3AB and KIF3AC ( 26 ). The single molecule results showed that the average distance these kinesins could step decreased 40–60% with EC 50 values <100 n m propofol with no effect on the velocity of movement.…”

Section: Introductionmentioning

confidence: 97%

“…These results indicate that propofol is not binding at the ATP-binding site or allosteric sites that modulate microtubule-activated ATP turnover. Rather, the results suggest that during a processive step on the microtubule, an allosteric binding site for propofol forms, propofol binds and disrupts the kinesin–microtubule interaction, and therefore results in kinesin detachment to end the processive run ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules

Woll

Guzik-Lendrum

Bensel

et al. 2018

Journal of Biological Chemistry

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Microtubule-based molecular motors mediate transport of intracellular cargo to subdomains in neurons. Previous evidence has suggested that the anesthetic propofol decreases the average run-length potential of the major anterograde transporters kinesin-1 and kinesin-2 without altering their velocity. This effect on kinesin has not been observed with other inhibitors, stimulating considerable interest in the underlying mechanism. Here, we used a photoactive derivative of propofol, meta-azipropofol (AziPm), to search for potential propofol-binding sites in kinesin. Single-molecule motility assays confirmed that AziPm and propofol similarly inhibit kinesin-1 and kinesin-2. We then applied AziPm in semiquantitative radiolabeling and MS microsequencing assays to identify propofol-binding sites within microtubule–kinesin complexes. The radiolabeling experiments suggested preferential AziPm binding to the ATP-bound microtubule–kinesin complex. The photolabeled residues were contained within the kinesin motor domain rather than at the motor domain–β-tubulin interface. No residues within the P-loop of kinesin were photolabeled, indicating an inhibitory mechanism that does not directly affect ATPase activity and has an effect on run length without changing velocity. Our results also indicated that when the kinesin motor interacts with the microtubule during its processive run, a site forms in kinesin to which propofol can then bind and allosterically disrupt the kinesin–microtubule interaction, resulting in kinesin detachment and run termination. The discovery of the propofol-binding allosteric site in kinesin may improve our understanding of the strict coordination of the motor heads during the processive run. We hypothesize that propofol's potent effect on intracellular transport contributes to various components of its anesthetic action.

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“…Should these tracks be decorated with bound anesthetic molecules, it is plausible that motor function and ultimately transport would be altered. In single-molecule experiments, where, instead of its usual cargo, kinesin is attached to a fluorescent bead and microtubules are immobilized on a substrate, it was noticed that clinically relevant concentrations of propofol reduced run length by half and had no effect on velocity 78 . In other words, the train goes just as fast but derails.…”

Section: Other Molecular Targets Of Propofolmentioning

confidence: 99%

Recent progress on the molecular pharmacology of propofol

Tang

Eckenhoff

2018

F1000Res

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The precise mechanism by which propofol enhances GABAergic transmission remains unclear, but much progress has been made regarding the underlying structural and dynamic mechanisms. Furthermore, it is now clear that propofol has additional molecular targets, many of which are functionally influenced at concentrations achieved clinically. Focusing primarily on molecular targets, this brief review attempts to summarize some of this recent progress while pointing out knowledge gaps and controversies. It is not intended to be comprehensive but rather to stimulate further thought, discussion, and study on the mechanisms by which propofol produces its pleiotropic effects.

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Common general anesthetic propofol impairs kinesin processivity

Cited by 26 publications

References 71 publications

Structural basis of human kinesin-8 function and inhibition

Structural basis of human kinesin-8 function and inhibition

An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules

Recent progress on the molecular pharmacology of propofol

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