Abstract
ABSTRACTKinesins are P‐loop NTPases that can do mechanical work. Like small G‐proteins, to which they are related, kinesins execute a program of active site conformational changes that cleaves the terminal phosphate from an NTP substrate. But unlike small G‐proteins, kinesins can amplify and harness these conformational changes in order to exert force. In this short review I summarize current ideas about how the kinesin active site works and outline how the active site chemistry is coupled to the larger‐scale structural cycle of the kinesin motor domain. Focusing largely on kinesin‐1, the best‐studied kinesin, I discuss how the active site switch machinery of kinesin cycles between three distinct states, how docking of the neck linker stabilizes two of these states, and how tension‐sensitive and position‐sensitive neck linker docking may modulate both the hydrolysis step of ATP turnover and the trapping of product ADP in the active site. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 476–482, 2016.
Highlights
E ukaryotic cells contain networks of microtubules that serve as railways for the motor-driven transport of cellular components
This connectedness, termed mechanochemical coupling, works reciprocally—it allows chemical kinetic events in the kinesin active site to be harnessed to drive a larger scale conformational cycle that in turn can do substantial work, and it allows external forces sensed by the motor to influence the chemical kinetics of ATP turnover
Phosphate release regenerates the weak K.ADP state[1] which shows the greatest tendency to detach from the microtubule. This mapping of nucleotide states to binding states appears to be broadly the same for all kinesins so far examined, the rates of ATP turnover, the fraction of time spent in each state and the effects of microtubules and unpolymerized tubulin on the rate constants for transitions vary widely—for example in kinesin-13, a depolymerase kinesin, the K.ADP state is still the detaching state, but the binding of unpolymerized tubulin seems to be required for hydrolysis.[2,3]
Summary
E ukaryotic cells contain networks of microtubules that serve as railways for the motor-driven transport of cellular components. Most kinesins haul molecular cargo directionally along microtubules, but some are specialized to control the assembly dynamics of their microtubule tracks, and a few can do both These two distinct activities, hauling cargo along microtubules and biasing subunit exchange at microtubule tips, are linked by a common thread, the generation and sensing of mechanical force in the kinesin active site. I review how the kinesin active site processes ATP and outline how its conformational programme can both drive and be driven by the larger-scale conformational programme of the motor as a whole. To do this I focus largely on kinesin-1, the best studied kinesin.
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