Kinesin motility is driven by subdomain dynamics
Texas A&M University, United States Korea Institute for Advanced Study, Korea Vanderbilt University, United States Vanderbilt University School of Medicine, United States Harvard University, United States ISIS, Université de Strasbourg, France
RESEARCH ARTICLE Nov 7, 2017
Motility of a Kin-1 dimer driven by subdomain dynamics.
Abstract
The microtubule (MT)-associated motor protein kinesin utilizes its conserved ATPase head to achieve diverse motility characteristics. Despite considerable knowledge about how its ATPase activity and MT binding are coupled to the motility cycle, the atomic mechanism of the core events remain to be found. To obtain insights into the mechanism, we performed 38.5 microseconds of all-atom molecular dynamics simulations of kinesin-MT complexes in different nucleotide states. Local subdomain dynamics were found to be essential for nucleotide processing. Catalytic water molecules are dynamically organized by the switch domains of the nucleotide binding pocket while ATP is torsionally strained. Hydrolysis products are 'pulled' by switch-I, and a new ATP is 'captured' by a concerted motion of the α0/L5/switch-I trio. The dynamic and wet kinesin-MT interface is tuned for rapid interactions while maintaining specificity. The proposed mechanism provides the flexibility necessary for walking in the crowded cellular environment.
https://doi.org/10.7554/eLife.28948.001
eLife digest
Motor proteins called kinesins perform a number of different roles inside cells, including transporting cargo and organizing filaments called microtubules to generate the force needed for a cell to divide. Kinesins move along the microtubules, with different kinesins moving in different ways: some ‘walk’, some jump, and some destroy the microtubule as they travel along it. All kinesins power their movements using the same molecule as fuel – adenosine triphosphate, known as ATP for short.
Energy stored in ATP is released by a chemical reaction known as hydrolysis, which uses water to break off specific parts of the ATP molecule. The site to which ATP binds in a kinesin has a similar structure to the ATP binding site of many other proteins that use ATP. However, little was known about the way in which kinesin uses ATP as a fuel, including how ATP binds to kinesin and is hydrolyzed, and how the products of hydrolysis are released. These events are used to power the motor protein.
Hwang et al. have used powerful computer simulation methods to examine in detail how ATP interacts with kinesin whilst moving across a microtubule. The simulations suggest that regions (or 'domains') of kinesin near the ATP binding site move around to help in processing ATP. These kinesin domains trap a nearby ATP molecule from the environment and help to deliver water molecules to ATP for hydrolysis. Hwang et al. also found that the domain motion subsequently helps in the release of the hydrolysis products by kinesin.
The domains around the ATP pocket vary among the kinesins and these differences may enable kinesins to fine-tune how they use ATP to move. Further investigations will help us understand why different kinesin families behave differently. They will also contribute to exploring how kinesin inhibitors might be used as anti-cancer drugs.
https://doi.org/10.7554/eLife.28948.002
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