Microtubule orientation and spacing within bundles is critical for long‐range kinesin‐1 motility

Conway, Leslie; Gramlich, Michael; Tabei, S. M. Ali; Ross, Jennifer L.

doi:10.1002/cm.21197

Cited by 25 publications

(35 citation statements)

References 44 publications

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“…In agreement with previous research, we first show that axonal projections have a higher GTP-tubulin density as compared to dendrites 21 This could be linked to the fact that kinesin motors bound to cargo have more difficulty traversing obstacles owing to their limited step-size and short neck-linker as compared to dynein motors [51][52][53][54] . Increasing the amount of stable, elongated tubulin dimers in neurons also led to increased anterograde-but without affecting retrograde velocities.…”

Section: Discussionsupporting

confidence: 91%

Nano-positioning and tubuline conformation determine transport of mitochondria along microtubules

Steenbergen

Lavoie-Cardinal

Kazwiny³

et al. 2020

Preprint

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Correct spatiotemporal distribution of organelles and vesicles is crucial for healthy cell functioning and is regulated by intracellular transport mechanisms. Controlled transport of bulky mitochondria is especially important in polarized cells such as neurons that rely on these organelles to locally produce energy and buffer calcium.Mitochondrial transport requires and depends on microtubules which fill much of the available axonal space. How mitochondrial transport is affected by their position within the microtubule bundles is not known. Here, we found that anterograde transport, driven by kinesin motors, is susceptible to the molecular conformation of tubulin both in vitro and in vivo. Anterograde velocities negatively correlate with the density of elongated tubulin dimers, similar to GTP-tubulin, that are more straight and rigid. The impact of the tubulin conformation depends primarily on where a mitochondrion is positioned, either within or at the rim of microtubule bundle. Increasing elongated tubulin levels lowers the number of motile anterograde mitochondria within the microtubule bundle and increases anterograde transport speed at the microtubule bundle rim. We demonstrate that the increased kinesin step processivity on microtubules consisting of elongated dimers underlies increased mitochondrial dynamics. Our work indicates that the molecular conformation of tubulin controls mitochondrial motility and as such locally regulates the distribution of mitochondria along axons.

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Section: Discussionsupporting

confidence: 91%

Nano-positioning and tubuline conformation determine transport of mitochondria along microtubules

Steenbergen

Lavoie-Cardinal

Kazwiny³

et al. 2020

Preprint

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“…4C). Prior work has shown that kinesin-1 motors have difficulty navigating obstacles such as microtubule-associated proteins and other roadblocks164344.…”

Section: Resultsmentioning

confidence: 99%

Single Molecule Investigation of Kinesin-1 Motility Using Engineered Microtubule Defects

Gramlich

Conway

Liang

et al. 2017

Sci Rep

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The structure of the microtubule is tightly regulated in cells via a number of microtubule associated proteins and enzymes. Microtubules accumulate structural defects during polymerization, and defect size can further increase under mechanical stresses. Intriguingly, microtubule defects have been shown to be targeted for removal via severing enzymes or self-repair. The cell’s control in defect removal suggests that defects can impact microtubule-based processes, including molecular motor-based intracellular transport. We previously demonstrated that microtubule defects influence cargo transport by multiple kinesin motors. However, mechanistic investigations of the observed effects remained challenging, since defects occur randomly during polymerization and are not directly observable in current motility assays. To overcome this challenge, we used end-to-end annealing to generate defects that are directly observable using standard epi-fluorescence microscopy. We demonstrate that the annealed sites recapitulate the effects of polymerization-derived defects on multiple-motor transport, and thus represent a simple and appropriate model for naturally-occurring defects. We found that single kinesins undergo premature dissociation, but not preferential pausing, at the annealed sites. Our findings provide the first mechanistic insight to how defects impact kinesin-based transport. Preferential dissociation on the single-molecule level has the potential to impair cargo delivery at locations of microtubule defect sites in vivo.

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“…In vitro, microtubule bundles obtained via excluded-volume interactions under macromolecular crowding conditions are tightly packed with wall-to-wall contacts, in contrast with the regularly spaced microtubules observed in tau-mediated bundles [30]. Microtubule-based transport should most probably be impaired in such compacted structures [45], which would be detrimental for most axonal functions.…”

Section: Resultsmentioning

confidence: 99%

Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding

Mephon-Gaspard

Boca

Pioche−Durieu

et al. 2016

Cell. Mol. Life Sci.

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Opposing views have been proposed regarding the role of tau, the principal microtubule-associated protein in axons. On the one hand, tau forms cross-bridges at the interface between microtubules and induces microtubule bundling in neurons. On the other hand, tau is also considered a polymer brush which efficiently separates microtubules. In mature axons, microtubules are indeed arranged in parallel arrays and are well separated from each other. To reconcile these views, we developed a mechanistic model based on in vitro and cellular approaches combined to analytical and numerical analyses. The results indicate that tau forms long-range cross-bridges between microtubules under macromolecular crowding conditions. Tau cross-bridges prevent the redistribution of tau away from the interface between microtubules, which would have occurred in the polymer brush model. Consequently, the short-range attractive force between microtubules induced by macromolecular crowding is avoided and thus microtubules remain well separated from each other. Interestingly, in this unified model, tau diffusion on microtubules enables to keep microtubules evenly distributed in axonal sections at low tau levels.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2216-z) contains supplementary material, which is available to authorized users.

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Microtubule orientation and spacing within bundles is critical for long‐range kinesin‐1 motility

Cited by 25 publications

References 44 publications

Nano-positioning and tubuline conformation determine transport of mitochondria along microtubules

Nano-positioning and tubuline conformation determine transport of mitochondria along microtubules

Single Molecule Investigation of Kinesin-1 Motility Using Engineered Microtubule Defects

Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding

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