Mechanistic basis of propofol-induced disruption of kinesin processivity

Abstract

Propofol is a widely used general anesthetic to induce and maintain anesthesia, and its effects are thought to occur through impact on the ligand-gated channels including the GABAA receptor. Propofol also interacts with a large number of proteins including molecular motors and inhibits kinesin processivity, resulting in significant decrease in the run length for conventional kinesin-1 and kinesin-2. However, the molecular mechanism by which propofol achieves this outcome is not known. The structural transition in the kinesin neck-linker region is crucial for its processivity. In this study, we analyzed the effect of propofol and its fluorine derivative (fropofol) on the transition in the neck-linker region of kinesin. Propofol binds at two crucial surfaces in the leading head: one at the microtubule-binding interface and the other in the neck-linker region. We observed in both the cases the order–disorder transition of the neck-linker was disrupted and kinesin lost its signal for forward movement. In contrast, there was not an effect on the neck-linker transition with propofol binding at the trailing head. Free-energy calculations show that propofol at the microtubule-binding surface significantly reduces the microtubule-binding affinity of the kinesin head. While propofol makes pi–pi stacking and H-bond interactions with the propofol binding cavity, fropofol is unable to make a suitable interaction at this binding surface. Therefore, the binding affinity of fropofol is much lower compared to propofol. Hence, this study provides a mechanism by which propofol disrupts kinesin processivity and identifies transitions in the ATPase stepping cycle likely affected.

Propofol attenuates kinesin-mediated axonal vesicle transport and fusion

“…, 2017 ; Woll et al. , 2018 ; Dutta et al. , 2021 ), we used a labeling strategy that we recently developed to visualize vesicle-bound Kinesin-1 family member KIF5C ( Yang et al.…”

“…Further work found that propofol reduces run lengths by binding to the leading head of microtubule-bound kinesins, increasing the probability of dissociation before the lagging head can complete a step ( Woll et al. , 2018 ; Dutta et al. , 2021 ).…”

“…Because the propofol binding pocket forms only when the leading kinesin motor domain is an ATP state and bound to the microtubule, motor dissociation results in propofol release ( Woll et al. , 2018 ; Dutta et al. , 2021 ).…”

Probing allosteric regulations with coevolution-driven molecular simulations

“…The molecular underpinnings of allosteric changes in protein structures are often hindered by averaged metrics, the transient nature of the species involved (8), the difficulty to reproduce biological events in vitro (9), or the great deal of computational power required to model uncharted free-energy surfaces (9,10). Nonetheless, allosteric regulations are widespread in biology (11)(12)(13)(14)(15)(16)(17)(18), and the characterization of the underlying free energy is critical to understand and control the functional conformational landscape of biomolecules (19). The objective of this work is thus to devise a computational procedure to efficiently explore the functional freeenergy landscape of a protein with and without the allosteric effector bound, thereby gaining insight into how conformational equilibria translates into function.…”

Continuous midazolam infusion can minimize the pro-inflammatory response to anesthesia and surgery for pediatric patients with intra-abdominal infection: Comparative study versus continuous propofol infusion

“…Propofol is an intravenous general anesthetic widely used for general anesthesia and for sedation in ICU [10]. Propofol acts by binding to and modulating several neuronal ion channels and its effects are thought to occur through an impact on the ligand-gated channels including the GABA A receptor [11].…”