Moonlighting Motors: Kinesin, Dynein, and Cell Polarity

Lü, Wen; Gelfand, Vladimir I.

doi:10.1016/j.tcb.2017.02.005

Cited by 96 publications

(77 citation statements)

References 68 publications

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“…Moreover, kinesin and dynein are the main motor proteins that traffic intracellular cargo along microtubules, including vesicles, organelles, protein complexes, and mRNA. 31 Previous studies revealed that disassembling microtubules leads to dysfunction in kinesin-and dynein-driven axonal transport with central nervous system injury or neurodegenerative diseases, and this compromised axonal transport is closely associated with early neurological dysfunction in ICH. 32 Similarly, we found that expression of kinesin and dynein was significantly decreased following disruption of microtubules in damaged dopamine neurons; this indicates that axonal transport in the nigrostriatal pathway was damaged.…”

Section: Discussionmentioning

confidence: 99%

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Yang

Zhang

et al. 2018

JAHA

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BackgroundMany previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH).Methods and ResultsIntrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice. Immunofluorescence, Western blotting, electron microscopy, functional behavioral tests, and anterograde and retrograde neural circuit tracking techniques were used in these mice. The data showed that the number of dopamine neurons and the dopamine concentration were severely decreased and that fine motor function was impaired after ICH. Microtubule depolymerization was the main contributor to the loss of dopamine neurons and to motor function deficits after ICH, as was also proven by intrastriatal injection of nocodazole. Moreover, administration of the microtubule stabilizer epothilone B (1.5 mg/kg) improved the integrity of the nigrostriatal pathway neural circuit, increased the number of dopamine neurons (4598±896 versus 3125±355; P=0.034) and the dopamine concentration (4.28±0.99 versus 3.08±0.75 ng/mg; P=0.041), and enhanced fine motor functional recovery associated with increased acetylated α‐tubulin expression to maintain microtubule stabilization after ICH.ConclusionsOur results clarified the pathomorphological changes of the nigrostriatal pathway after ICH and found that epothilone B helped alleviate nigrostriatal pathway injury after ICH, associated with promoting α‐tubulin acetylation to maintain microtubule stabilization, thus facilitating motor recovery.

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Section: Discussionmentioning

confidence: 99%

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Yang

Zhang

et al. 2018

JAHA

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“…1b [8,9]. Parallel array of MTs, acting as reinforcing components with a main function of transporting electrochemical cargo, are the stiffest structural element within the axon [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Mathematical modelling of microtubule-tau protein transients: Insights into the superior mechanical behavior of axon

Yuan

et al. 2019

Applied Mathematical Modelling

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Axons with staggered microtubules cross-linked by tau protein possess a remarkable mechanical balance of high specific stiffness and toughness. Owing to their viscoelastic nature, axons exhibit stress rate-dependent mechanical behavior, which is relevant to their selective vulnerability to damage in traumatic brain injury. A Kelvin-Voigt viscoelastic shear lag model is developed to elucidate the mechanical responses of axons under transient tensile force. Analytical closed-form expressions are derived to characterize the relative sliding, stress transfer and failure mechanism between microtubule and tau protein while the axon is stretched transiently. The results from the theoretical solutions elucidate how the MT-tau interface length and stress rate affect the mechanical responses of axon. It is found that axonal failure mechanism may be different under different loading conditions. Long microtubules are more vulnerable to rupture at high stress rate, yet short microtubules are likely to detach from microtubule bundles under large deformations. In the view of multi-level failure of axon, it is illustrated how the vulnerable axons protect themselves from overall damage, and how the axon can simultaneously achieve an outstanding mechanical balance of high specific stiffness and toughness.

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“…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)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16).…”

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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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Moonlighting Motors: Kinesin, Dynein, and Cell Polarity

Cited by 96 publications

References 68 publications

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Mathematical modelling of microtubule-tau protein transients: Insights into the superior mechanical behavior of axon

Kinesin-2 motors: Kinetics and biophysics

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