A universal pathway for kinesin stepping

Clancy, Bason; Behnke-Parks, William M.; Andreasson, Johan O. L.; Rosenfeld, Steven S.; Block, Steven M.

doi:10.1038/nsmb.2104

Cited by 196 publications

(396 citation statements)

References 48 publications

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“…However, many models parametrized to experimental biomolecular machine dynamics contain effectively irreversible transitions [16][17][18][19][20][21][22], suggesting that some transitions dissipate a large amount of free energy compared to the 'reversible' transitions in the same cycle.…”

Section: Introductionmentioning

confidence: 99%

Allocating dissipation across a molecular machine cycle to maximize flux

Brown

Sivak

2017

Proc. Natl. Acad. Sci. U.S.A.

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Biomolecular machines consume free energy to break symmetry and make directed progress. Nonequilibrium ATP concentrations are the typical free energy source, with one cycle of a molecular machine consuming a certain number of ATP, providing a fixed free energy budget. Since evolution is expected to favor rapid-turnover machines that operate efficiently, we investigate how this free energy budget can be allocated to maximize flux. Unconstrained optimization eliminates intermediate metastable states, indicating that flux is enhanced in molecular machines with fewer states. When maintaining a set number of states, we show that-in contrast to previous findings-the fluxmaximizing allocation of dissipation is not even. This result is consistent with the coexistence of both 'irreversible' and reversible transitions in molecular machine models that successfully describe experimental data, which suggests that in evolved machines different transitions differ significantly in their dissipation.

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Section: Introductionmentioning

confidence: 99%

Allocating dissipation across a molecular machine cycle to maximize flux

Brown

Sivak

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…While straightforward in developing a formalism, the unicyclic reaction scheme leads to a problematic interpretation that the backstep is realized always by a reversal of the forward cycle [24], which means that the backstep near stall condition is taken with the synthesis of ATP from ADP and P i . This rather strong assumption could be alleviated by extending the current formalism to the one based on a multi-cycle model [14,24,35,36], so as to accommodate the possibilities of ATP-induced backstep and futile cycle near the stall condition. For multiple cycle model, the flux branches into different cycles and the net flux at each kinetic step remains nonvanishing (j + = j − ) even at stall condition.…”

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confidence: 99%

Quantifying the Heat Dissipation from Molecular Motor’s Transport Properties in Nonequilibrium Steady States

Hwang

Hyeon

2016

Preprint

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Theoretical analysis, which maps single molecule time trajectories of a molecular motor onto unicyclic Markov processes, allows us to evaluate the heat dissipated from the motor and to elucidate its dependence on the mean velocity and diffusivity. Unlike passive Brownian particles in equilibrium, the velocity and diffusion constant of molecular motors are closely inter-related to each other. In particular, our study makes it clear that the increase of diffusivity with the heat production is a natural outcome of active particles, which is reminiscent of the recent experimental premise that the diffusion of an exothermic enzyme is enhanced by the heat released from its own catalytic turnover. Compared with freely diffusing exothermic enzymes, kinesin-1 whose dynamics is confined on one-dimensional tracks is highly efficient in transforming conformational fluctuations into a locally directed motion, thus displaying a significantly higher enhancement in diffusivity with its turnover rate. Putting molecular motors and freely diffusing enzymes on an equal footing, our study offers thermodynamic basis to understand the heat enhanced self-diffusion of exothermic enzymes.Together with recent studies [1][2][3][4], Riedel et al. [5] have demonstrated a rather surprising result, from a perspective of equilibrium statistical mechanics: Diffusion constants (D) of exothermic enzymes, measured from fluorescence correlation spectroscopy (FCS), increase linearly with their catalytic turnover rates V cat , so that the enhancement of diffusivity at maximal activity (maximum V cat ) is as large aswhere D 0 and D max are the diffusion constants measured by FCS at V cat = 0 and maximal V cat , respectively. Their enigmatic observation [5] has called much attention of biophysics community to the physical origin of the activity-dependent diffusivity of a single enzyme. Golestanian [6] considered four distinct scenarios (self-thermophoresis, boost in kinetic energy, stochastic swimming, collective heating) to account for this observation quantitatively; however, the extent of enhancement observed in the experiment was still orders of magnitude greater than the theoretical estimates from the suggested mechanisms. Bai et al.[7] also drew a similar conclusion by considering hydrodynamic coupling between the conformational change of enzyme and surrounding media. The experimental demonstration of enzymes' enhanced diffusion with multiple control experiments in Ref.[5] is straightforward; however, physical insight of the observed phenomena is currently missing [5,6,8,9].While seemingly entirely different from freely diffusing enzymes, kinesin-1 [10-15] is also a substrate-catalyzing enzyme. Conformational dynamics of kinesin-1, induced by ATP hydrolysis and thermal fluctuations, is rectified into a unidirectional movement with a high fidelity [16,17]; hydrolysis of a single ATP almost always leads to 8 nm step [18]. Every step of kinesin-1 along 1D tracks, an outcome of cyclic chemical reaction, can be mapped (2)µ, ..., (N )µ denote distinc...

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“…The significance of the findings reported here is the conclusion that the key principles for force generation by kinesin-14s are evolutionarily conserved from yeast to higher eukaryotes. In addition, the results show conclusively that for Ncd, two ATP turnovers are required to generate a single powerstroke displacement or step in contrast to conventional myosin II (33) and the processive myosins and kinesins, which require only a single ATP turnover for each step (34,35). Therefore, this study implicates the homodimeric kinesin-14s as a novel class of molecular motors where two ATP turnover events are required for each powerstroke-driven microtubule displacement or step.…”

Section: Discussionmentioning

confidence: 65%

Drosophila Ncd reveals an evolutionarily conserved powerstroke mechanism for homodimeric and heterodimeric kinesin-14s

Zhang¹,

Dai

Hahn

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Drosophila melanogaster kinesin-14 Ncd cross-links parallel microtubules at the spindle poles and antiparallel microtubules within the spindle midzone to play roles in bipolar spindle assembly and proper chromosome distribution. As observed for Saccharomyces cerevisiae kinesin-14 Kar3Vik1 and Kar3Cik1, Ncd binds adjacent microtubule protofilaments in a novel microtubule binding configuration and uses an ATP-promoted powerstroke mechanism. The hypothesis tested here is that Kar3Vik1 and Kar3Cik1, as well as Ncd, use a common ATPase mechanism for force generation even though the microtubule interactions for both Ncd heads are modulated by nucleotide state. The presteady-state kinetics and computational modeling establish an ATPase mechanism for a powerstroke model of Ncd that is very similar to those determined for Kar3Vik1 and Kar3-Cik1, although these heterodimers have one Kar3 catalytic motor domain and a Vik1/Cik1 partner motor homology domain whose interactions with microtubules are not modulated by nucleotide state but by strain. The results indicate that both Ncd motor heads bind the microtubule lattice; two ATP binding and hydrolysis events are required for each powerstroke; and a slow step occurs after microtubule collision and before the ATP-promoted powerstroke. Note that unlike conventional myosin-II or other processive molecular motors, Ncd requires two ATP turnovers rather than one for a single powerstroke-driven displacement or step. These results are significant because all metazoan kinesin-14s are homodimers, and the results presented show that despite their structural and functional differences, the heterodimeric and homodimeric kinesin-14s share a common evolutionary structural and mechanochemical mechanism for force generation.presteady-state kinetics | dynamic modeling | microtubules I n the early stages of mitosis and meiosis, the bipolar metaphase spindle must be established, and kinesin-14 molecular motors play key roles in this process (1-4). In contrast to the microtubule (MT) plus-end directed processive kinesins, kinesin-14s are not processive as single molecules; they promote MT minus-enddirected force and use an ATP-promoted powerstroke to crosslink and slide one MT relative to another (5-17). Sequence analysis indicates that all members of the kinesin-14 subfamily are dimeric, yet the structural organization of kinesin-14 motors differs from the N-terminal processive kinesins. The kinesin-14s exhibit C-terminal motor domains connected by an N-terminal continuous coiled-coil stalk with an N-terminal ATP-independent MT binding site (7,(18)(19)(20)(21)(22). And although most of the kinesin-14s are homodimeric, some yeast species, including Saccharomyces cerevisiae and Candida glabrata, contain heterodimeric kinesin-14s (13,14,19). The conventional hypothesis for homodimeric kinesin-14 force generation proposed that only one motor head interacts with the MT and only one ATP turnover is required to complete the powerstroke (Fig. S1A) (10, 12). In contrast, our presteady-state kinetics (9,...

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A universal pathway for kinesin stepping

Cited by 196 publications

References 48 publications

Allocating dissipation across a molecular machine cycle to maximize flux

Allocating dissipation across a molecular machine cycle to maximize flux

Quantifying the Heat Dissipation from Molecular Motor’s Transport Properties in Nonequilibrium Steady States

Drosophila Ncd reveals an evolutionarily conserved powerstroke mechanism for homodimeric and heterodimeric kinesin-14s

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