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An Animated Model for Processive Motility by Conventional Kinesin



An animated model for processive motility by conventional kinesin The two heads of the kinesin dimer work in a coordinated manner to move processively along the microtubule. The catalytic core (blue) is bound to a tubulin heterodimer (green, ß subunit; white, A subunit) along a microtubule protofilament (the cylindrical microtubule is composed of 13 protofilament tracks). In solution, both kinesin heads contain ADP in the active site (ADP release is rate-limiting in the absence of microtubules). The chaotic motion of the kinesin molecule reflects Brownian motion. One kinesin head makes an initial weak binding interaction with the microtubule and then rearranges to engage in a tight binding interaction. Only one kinesin head can readily make this tight interaction with the microtubule, due to restraints imposed by the coiled-coil and pre-stroke conformation of the neck linker in the bound head. Microtubule binding releases ADP from the attached head. ATP then rapidly enters the empty nucleotide-binding site, which triggers the neck linker to zipper onto the catalytic core (red to yellow transition). This action throws the detached head forward and allows it to reach the next tubulin binding site, thereby creating a 2-head-bound intermediate in which the neck linkers in the trailing and leading heads are pointing forward (post-stroke; yellow) and backwards (pre-stroke; red) respectively. The trailing head hydrolyzes the ATP (yellow flash of ADP-Pi), and reverts to a weak microtubule binding state (indicated by the bouncing motion) and releases phosphate (fading Pi). Phosphate release also causes the unzippering of the neck linker (yellow to red transition). The exact timing of the strong-to-weak microtubule binding transition and the phosphate release step are not well defined from current experimental data. During the time when the trailing head executes the previously described actions, the leading head releases ADP, binds ATP, and zippers its neck linker onto the catalytic core. This neck linker motion throws the trailing head forward by 160 Å to the vicinity of new tubulin binding site. After a random diffusional search, the new lead head docks tightly onto the binding site, which completes the 80 Å step of the motor. The movie shows two such 80 Å steps of the kinesin motor. The surface features of the kinesin motor domains and the microtubule protofilament were rendered from X-ray and EM crystallographic structures by Graham Johnson (fiVth media: www.fiVth.com) using the programs MolView, Strata Studio Pro and Cinema 4D. PDB files used were human conventional kinesin (prestroke, red: #1BG2) and rat conventional kinesin (poststroke, yellow: #2KIN). In human conventional kinesin, the neck linker is mobile and its located in the prestroke state is estimated from cryo-electron microscopy data. Transitions between states are computer-coordinated extrapolations between the prestroke and poststroke positions. The durations of the events in this sequence were optimized for clarity and do not necessarily reflect the precise timing of events in the ATPase cycle.


Contact information:

Ron Vale (vale@phy.ucsf.edu)
Ron Milligan (milligan@scripps.edu)
Graham Johnson (graham@fiVth.com)


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