Intraflagellar transport velocity is governed by the number of active KIF17 and KIF3AB motors and their motility properties under load

Milic, Bojan; Andreasson, Johan O. L.; Hogan, Daniel W.; Block, Steven M.

doi:10.1073/pnas.1708157114

Cited by 56 publications

(78 citation statements)

References 78 publications

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“…Moreover, the authors stated that there was no evidence that force sensitivity was encoded in the neck linker (86). In addition, Milic et al reported that kinesin-2 KIF17 continues to step under a 6-pN hindering load whereas KIF3AB detaches from the microtubule at these conditions (87). Note that the neck linker motif of KIF17 is almost identical in sequence to that of KIF3A and KIF3B (Fig.…”

Section: Structural Studies Show That the Coiled-coil Predictions Wermentioning

confidence: 99%

Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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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 review, 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.Kinesins constitute a superfamily of microtubule-based molecular motor enzymes that couple the chemical energy from ATP turnover to force production for diverse cellular functions (reviewed in (1-12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16). However, key amino acid residue changes can confer unique mechanochemical properties to each kinesin, which in turn specify cellular function. The N-terminal kinesins are composed of an N-terminal motor domain connected to a long a-helical region that dimerizes into a coiled-coil stalk that ends with a C-terminal domain that may interact with specific adaptor proteins for cargo linkage (Fig. 1). N-kinesin subfamilies include conventional kinesin-1, kinesin-2, kinesin-3, kinesin-5 Eg5/KSP, and kinesin-7 CENP-E, and all are best known for their roles in intracellular transport.N-kinesins carry cargo directionally toward the plus-end of microtubules, which are polymerized from ab-tubulin subunits to form a cylindrical polymer of 13 protofilaments. The kinesins are able to "read" the polarity of the microtubule because of the structural asymmetry of ab-tubulin subunits. The movement of N-kinesins is designated as "processive," which implies that upon microtubule collision, a single, dimeric kinesin steps continuously toward the microtubule plus end in an asymmetric hand-over-hand manner hydrolyzing one ATP per 8-nm step for hundreds of steps (17)(18)(19)(20)(21)(22). The 8-nm step size results from the distance between adjacent ab-tubulin dimers along the microtubule lattice. As Fig. 2 illustrates, a processive kinesin binds the microtubule and then goes through a series of structural transitions, each modulated by nucleotide state. To maintain a processive run with continuous stepping, the Kinesin-2 Molecular Motors 2ATPase cycle of each head remains out-of-phase with the other to avoid premature release if both heads exist in a microtubule weak binding state simultaneously. The degree of processivity, quantified by "run length," varies between kinesin subfamilies and is regulated by a series of "gating" mechanisms in which a chemical and/or mechanical requirement must be satisfied to proceed forward. There has been significant effort to define the determinants of ...

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Section: Structural Studies Show That the Coiled-coil Predictions Wermentioning

confidence: 99%

Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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“…To quantify their motility properties, we digitized single-molecule motility data from Ref. [32] and fitted them to the 6-state double-cycle model (Figs. S6, S8) (See SI for detail).…”

Section: Comparison Of Q Between Different Types Of Kinesinsmentioning

confidence: 99%

Energetic costs, precision, and efficiency of a biological motor in cargo transport

Hwang

Hyeon

2017

Preprint

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Molecular motors play key roles in organizing the interior of cells. An efficient motor in cargo transport would travel with a high speed and a minimal error in transport time (or distance) while consuming minimal amount of energy. The travel distance and its variance of motor are, however, physically constrained by energy consumption, the principle of which has recently been formulated into the thermodynamic uncertainty relation. Here, we reinterpret the uncertainty measure (Q) defined in the thermodynamic uncertainty relation such that a motor efficient in cargo transport is characterized with a small Q. Analyses on the motility data from several types of molecular motors show that Q is a nonmonotic function of ATP concentration and load (f ). For kinesin-1, Q is locally minimized at [ATP] ≈ 200 µM and f ≈ 4 pN. Remarkably, for the mutant with a longer neck-linker this local minimum vanishes, and the energetic cost to achieve the same precision as the wild-type increases significantly, which underscores the importance of molecular structure in transport properties. For the biological motors studied here, their value of Q is semi-optimized under the cellular condition ([ATP] ≈ 1 mM, f = 0 − 1 pN). We find that among the motors, kinesin-1 at single molecule level is the most efficient in cargo transport.Biological systems are in nonequilibrium steady states (NESS) in which the energy and material currents flow constantly in and out of the system. Subjected to incessant thermal and nonequilibrium fluctuations, cellular processes are inherently stochastic and error-prone. To minimize detrimentaion effects, cells are equipped with a plethora of energy-consuming error-correction mechanisms. Trade-off relations between the energetic cost and information processing are ubiquitous in cellular processes, and have been a recurring theme in biology for many decades [1? ? -4].A recent study by Barato and Seifert [5] has formulated a concise inequality known as the thermodynamic uncertainty relation, the trade-off between energy consumption and precision of an observable from dissipative processes in NESS. To be more explicit, the uncertainty measure Q, defined as a product between the energy consumption (heat dissipation, Q(t)) from an energy-driven process in the steady state and the squared relative error of an output observable X(t), 2 X (t) = δX 2 / X 2 , is constant. It has been further conjectured that for an arbitrary chemical network formulated by Markov jump processes Q cannot be smaller than 2k B T ,The measure Q quantifies the uncertainty of a dynamic process. The smaller the value of Q, the more regular and predictable is the trajectory generated from the process, rendering the output observable more precise. The proof and physical significance of this inequality have been discussed [5][6][7][8][9][10]. In the presence of large fluctuations inherent to cellular processes, harnessing energy into precise motion is critical for accuracy in cellular computation.The uncertainty measure Q can be used to assess the e...

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“…In contrast to homodimeric kinesin-1, several members of the kinesin-2 subfamily form heterodimeric motors that further associate with a non-motor subunit to function as heterotrimeric motors in vivo [13]. Previous work on heterodimeric kinesin-2 revealed marked differences in processivity and force-dependent behavior when compared to kinesin-1 [14][15][16][17]. In contrast to kinesin-1, the kinesin-2 processivity precipitated under load, but in load-free fluorescence-based assays, kinesin-2 processivity matched that of kinesin-1 [16,17].…”

Section: Introductionmentioning

confidence: 99%

Kinesin‐2 motors adapt their stepping behavior for processive transport on axonemes and microtubules

et al. 2017

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Two structurally distinct filamentous tracks, namely singlet microtubules in the cytoplasm and axonemes in the cilium, serve as railroads for long-range transport processes In all organisms studied so far, the kinesin-2 family is essential for long-range transport on axonemes. Intriguingly, in higher eukaryotes, kinesin-2 has been adapted to work on microtubules in the cytoplasm as well. Here, we show that heterodimeric kinesin-2 motors distinguish between axonemes and microtubules. Unlike canonical kinesin-1, kinesin-2 takes directional, off-axis steps on microtubules, but it resumes a straight path when walking on the axonemes. The inherent ability of kinesin-2 to side-track on the microtubule lattice restricts the motor to one side of the doublet microtubule in axonemes. The mechanistic features revealed here provide a molecular explanation for the previously observed partitioning of oppositely moving intraflagellar transport trains to the A- and B-tubules of the same doublet microtubule. Our results offer first mechanistic insights into why nature may have co-evolved the heterodimeric kinesin-2 with the ciliary machinery to work on the specialized axonemal surface for two-way traffic.

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Intraflagellar transport velocity is governed by the number of active KIF17 and KIF3AB motors and their motility properties under load

Cited by 56 publications

References 78 publications

Kinesin-2 motors: Kinetics and biophysics

Kinesin-2 motors: Kinetics and biophysics

Energetic costs, precision, and efficiency of a biological motor in cargo transport

Kinesin‐2 motors adapt their stepping behavior for processive transport on axonemes and microtubules

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