Neck linker docking coordinates the kinetics of kinesin's heads

TL;DR

This paper presents a comprehensive kinetic model of kinesin motor proteins, explaining head coordination and force generation during movement by integrating structural and kinetic data, and predicting effects of modifications.

Contribution

It introduces the first detailed, thermodynamically consistent model of kinesin that explains head cooperation and reproduces experimental data across various conditions.

Findings

Model explains kinesin head coordination and gating mechanisms.

Reproduces experimental data such as speed and processivity.

Predicts effects of structural changes on kinesin motion.

Abstract

Conventional kinesin is a two-headed homodimeric motor protein, which is able to walk along microtubules processively by hydrolyzing ATP. Its neck linkers, which connect the two motor domains and can undergo a docking/undocking transition, are widely believed to play the key role in the coordination of the chemical cycles of the two motor domains and, consequently, in force production and directional stepping. Although many experiments, often complemented with partial kinetic modeling of specific pathways, support this idea, the ultimate test of the viability of this hypothesis requires the construction of a complete kinetic model. Considering the two neck linkers as entropic springs that are allowed to dock to their head domains and incorporating only the few most relevant kinetic and structural properties of the individual heads, here we develop the first detailed, thermodynamically consistent model of kinesin that can (i) explain the cooperation of the heads (including their gating mechanisms) during walking and (ii) reproduce much of the available experimental data (speed, dwell time distribution, randomness, processivity, hydrolysis rate, etc.) under a wide range of conditions (nucleotide concentrations, loading force, neck linker length and composition, etc.). Besides revealing the mechanism by which kinesin operates, our model also makes it possible to look into the experimentally inaccessible details of the mechanochemical cycle and predict how certain changes in the protein affect its motion.