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. 2015 Sep;7(3):269-299.
doi: 10.1007/s12551-014-0150-6. Epub 2015 Feb 13.

Kinesin Motor Enzymology: Chemistry, Structure, and Physics of Nanoscale Molecular Machines

J C Cochran  1
Affiliations

Kinesin Motor Enzymology: Chemistry, Structure, and Physics of Nanoscale Molecular Machines

J C Cochran. Biophys Rev. 2015 Sep.

Abstract

Molecular motors are enzymes that convert chemical potential energy into controlled kinetic energy for mechanical work inside cells. Understanding the biophysics of these motors is essential for appreciating life as well as apprehending diseases that arise from motor malfunction. This review focuses on kinesin motor enzymology with special emphasis on the literature that reports the chemistry, structure and physics of several different kinesin superfamily members.

Keywords: Chemical models; Enzymes; Kinesin motor enzymology; Kinesin superfamily; Molecular motors.

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Figures

Fig. 1
Fig. 1
Minimal ATPase mechanisms for monomeric and dimeric kinesins. Monomeric (a) and dimeric (b) kinesin ATPase mechanisms are shown. E kinesin, M microtubule, T ATP substrate, D ADP product, P i inorganic phosphate product, apo nucleotide-free/rigor. For dimeric kinesins that have two inter-molecularly regulated active sites, each site is depicted as either a superscript or subscript (for example: E• ADP• ADP indicates tha3 both sites of the dimeric kinesin (E) are bound to ADP)
Fig. 2
Fig. 2
Model for the kinesin-1 “hand-over-hand” walking mechanism. Molecular representations of the dimeric kinesin-1 motor and microtubule (MT) are shown in each of four states (labeled numbers to the left of figure). The coiled–coil stalk (gray) and neck linker (red) are highlighted in each state. Coloring of the kinesin motor core represents three structural states: dark blue strongly ADP-bound, weakly microtubule-bound, neck linker undocked; cyan weakly nucleotide-bound, strongly microtubule-bound, neck linker undocked; magenta strongly ATP- or ADP•Pi-bound, strongly microtubule-bound, neck linker docked. Dimeric kinesin-1 motors are purified with ADP tightly bound to both active sites. The first head to strongly interact with the microtubule (head 1) will rapidly release its bound ADP to reach the nucleotide-free/apo/rigor state (state 1). Since head 2 remains unattached to the microtubule, head 1 is able to bind ATP, which docks the neck linker of head 1, biasing head 2 forward (i.e., toward the MT plus-end) to the next binding site on the same MT protofilament (state 2). ATP hydrolysis on head 1 is concomitant with tight microtubule-binding by head 2 to rapidly release its ADP product (state 3). Upon Pi release from head 1, intramolecular strain coupled to conformational changes in the ADP state of head 1 lead to weakening of head 1’s interaction with the MT (state 3). After detachment of head 1 from the MT, the kinesin effectively reaches state 1 with the exception that the heads trade places (i.e., head 2 is nucleotide-free/apo/rigor while head 1 is ADP-bound and detached from the MT). The transition from state 3 to state 4 leads to a release of the intramolecular tension that is thought to provide a mechanical gating of ATP binding to the front head
Fig. 3
Fig. 3
Kinesin structure and topology. The monomeric human kinesin-1 structure (1BG2; Kull et al. 1996) is depicted in four distinct orientations: a front, b back, c left side, d right side. Secondary structure elements (α-helices, β-strands, and loops) are colored blue, gold, and red, respectively. Mg2+ and ADP are shown as space-fill model and are colored magenta and cyan, respectively. e Topology diagram of the kinesin motor domain shows α-helices (circles; shaded blue; up/down direction indicated by loop attachment), β-strands (triangles; shaded gold; up/down to depict orientation), and loops (red lines) as rendered from (Kull et al. 1998)
Fig. 4
Fig. 4
Structural changes in the eight-stranded central β-sheet of kinesin. Side (a) and end (b) views of the kinesin β-sheet after a nucleotide-bound structure (1BG2; Kull et al. 1996) was aligned with a rigor-like structure (4OZQ; Arora et al. 2014) using the main chain atoms of the P-loop. Mg2+ and ADP are shown as space-fill model and are colored magenta and cyan, respectively. c The root-mean-square deviation (RMSD) of complementary residues is plotted for each individual β-strand. d Individual β-strand curvature based on the sum of sequential Cα distances for each β-strand residue (i = initial residue, i + x = final residue) divided by the total distance from initial to final Cα∑ii+xDi→i+1Di→i+x plotted for nucleotide-bound and rigor-like structures. e β-strand torsion angles (τ) relative to β1 are plotted to quantify the degree of twisting within the entire β-sheet. Torsion angles were calculated using the following equation for each individual β-strand: τβ2=τβ1,β2=cos−1β1^⋅β2^, where β1^andβ2^ are the unit vectors for each respective β-strand (Cecchini et al. 2008). f The change in each individual β-strand torsion angle (Δτ) as the kinesin central β-sheet transitions from nucleotide-bound (1BG2) to rigor-like (4OZQ) states
Fig. 5
Fig. 5
Kinesin energy landscape in the absence and presence of microtubules. The energy landscapes for human monomeric kinesin-5 (Eg5) in the absence (black) and presence (red) of microtubules are shown. The thermodynamically and kinetically defined intermediate states are defined in the table. The magnitude of energy for each transition state was calculated from the Arrhenius/Eyring/Kramer equation k=kBThe−ΔG‡RT;kB=Boltzmannconstant,T=temperature,h=Planck'sconstant,R=gasconstant,ΔG‡=Gibb'stransitionstatefreeenergy using previously determined kinetic rate constants for the monomeric kinesin-5 ATPase mechanism (Table 1). Adapted and updated from Zhao et al. (2010)
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