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Review
. 2018 Mar 23;293(12):4510-4518.
doi: 10.1074/jbc.R117.001324. Epub 2018 Feb 14.

Kinesin-2 Motors: Kinetics and Biophysics

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Free PMC article
Review

Kinesin-2 Motors: Kinetics and Biophysics

Susan P Gilbert et al. J Biol Chem. .
Free PMC article

Abstract

Kinesin-2s are major transporters of cellular cargoes. This subfamily contains both homodimeric kinesins whose catalytic domains result from the same gene product and heterodimeric kinesins with motor domains derived from two different gene products. In this Minireview, we focus on the progress to define the biochemical and biophysical properties of the kinesin-2 family members. Our understanding of their mechanochemical capabilities has been advanced by the ability to identify the kinesin-2 genes in multiple species, expression and purification of these motors for single-molecule and ensemble assays, and development of new technologies enabling quantitative measurements of kinesin activity with greater sensitivity.

Keywords: ATPase; cilia; cytoskeleton; intracellular trafficking; microtubule; molecular motor; motor protein; neuron; pre-steady-state kinetics; processivity; single-molecule biophysics; tubulin.

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Molecular organization of kinesin-1, -2, -5, and -7 processive motors. These processive kinesins all contain two molecular motor domains, although the molecular organization of the remaining and associated polypeptide chains differs within and between kinesin subfamilies. The depictions shown here include representative space-filling models for domains whose three-dimensional structures are known and cartoons for those segments whose structures are yet to be determined. The lengths for the coiled-coiled and globular domains, whose structures have not been defined, are not drawn to scale. The X-ray coordinates used to generate this figure include the motor domains for kinesin-1, 3KIN; Eg5, 4PXU; CENP-E, 1T5C; KIF3B, 3B6U; KIF3C, 3B6V; and KIF17, 2VVG. The coordinates for the Eg5 BASS tetramerization domain and kinesin-1 light chain are 4PXU and 3CEQ, respectively.
Figure 2.
Figure 2.
KIF3 stepping models. Two variations of a kinesin stepping cycle are presented: a front-head–gated model (A), and a revised rear-head–gated model (B). Each cycle begins as one motor head collides with the microtubule; ADP is released, and the asymmetry of the ATPase cycle on each motor domain is established (E0–E1). The E1 intermediate is tightly bound to the microtubule with its leading head nucleotide-free and the trailing head detached as the weak-binding ADP state. A, ATP binds to the leading head and generates a structural transition transmitted through the neck-linker motif (E2–E3). The ATP-induced structural transition is designated neck-linker docking (*) and shifts the lagging unbound head forward by 16 nm to the next microtubule-binding site toward the microtubule plus-end (E2–E4). ADP is subsequently released (E4–E5). Both heads are bound to the microtubule with the leading head now nucleotide-free and tightly bound to the microtubule. ATP hydrolysis on the rear head (E5) results in another series of structural transitions in which phosphate is released; the trailing head transitions into a weakly bound ADP state and detaches from the microtubule to form the E1 intermediate. The first 8-nm step of the cycle is coupled to one ATP turnover and positions the new leading head to begin the second step of the processive run waiting for ATP (E1). The front-head–gated model (A) proposes that ATP binding promotes neck-linker docking that is coupled with a structural step (E2–E5) and that in the two-head bound state (E5), and ATP binding on the leading head is inhibited. In contrast, the revised rear-head–gated model (B) proposes that ATP binding partially docks the neck linker onto the catalytic core but posits that ATP hydrolysis (E2–E4) occurs while the tethered head is in its diffusional search for its microtubule-binding site with ATP hydrolysis required to completely dock the neck linker. The rear-head–gated model proposes that the E3–E4 intermediate is in a kinetic race for the front head to bind tightly to the microtubule before phosphate is released on the rear head (E4–E5).
Figure 3.
Figure 3.
Species-specific neck-linker length analysis and KIF3C loop L11 sequence motif. A, neck-linker sequence comparison for processive kinesins and neck-linker length predictions based on structural analysis (80). B, species-specific alignment of loop L11 sequences between KIF3A, KIF3B, and KIF3C in comparison with other processive kinesins. Red sequence represents the extended KIF3C-specific residues.

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