Detection of GTP-Tubulin Conformation in Vivo Reveals a Role for GTP Remnants in Microtubule Rescues

Dimitrov, Ariane; Quesnoit, Mélanie; Moutel, Sandrine; Cantaloube, Isabelle; Poüs, Christian; Perez, Franck

doi:10.1126/science.1165401

Cited by 244 publications

(306 citation statements)

References 19 publications

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“…Therefore one observes a so-called GTP cap at the growing plus-end of the microtubule, while further along the microtubule, most β-tubulins carry a GDP molecule. Still, 'islands' of GTP can be found inside polymerized MTs in vivo [95]. The relatively long lifetimes of these islands indicate that the stochastic process of GTP hydrolysis occurs on different time scales depending on whether the associated tubulin subunit is exposed at the plus-end or whether it is buried in the MT lattice.…”

Section: I E W Smentioning

confidence: 99%

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Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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Cells are the elementary units of living organisms, which are able to carry out many vital functions. These functions rely on active processes on a microscopic scale. Therefore, they are strongly out-of-equilibrium systems, which are driven by continuous energy supply. The tasks that have to be performed in order to maintain the cell alive require transportation of various ingredients, some being small, others being large. Intracellular transport processes are able to induce concentration gradients and to carry objects to specific targets. These processes cannot be carried out only by diffusion, as cells may be crowded, and quite elongated on molecular scales. Therefore active transport has to be organized.The cytoskeleton, which is composed of three types of filaments (microtubules, actin and intermediate filaments), determines the shape of the cell, and plays a role in cell motion. It also serves as a road network for a special kind of vehicles, namely the cytoskeletal motors. These molecules can attach to a cytoskeletal filament, perform directed motion, possibly carrying along some cargo, and then detach.It is a central issue to understand how intracellular transport driven by molecular motors is regulated. The interest for this type of question was enhanced when it was discovered that intracellular transport breakdown is one of the signatures of some neuronal diseases like the Alzheimer.We give a survey of the current knowledge on microtubule based intracellular transport. Our review includes on the one hand an overview of biological facts, obtained from experiments, and on the other hand a presentation of some modeling attempts based on cellular automata. We present some background knowledge on the original and variants of the TASEP (Totally Asymmetric Simple Exclusion Process), before turning to more application oriented models. After addressing microtubule based transport in general, with a focus on in vitro experiments, and on cooperative effects in the transportation of large cargos by multiple motors, we concentrate on axonal transport, because of its relevance for neuronal diseases. Some important characteristics of axonal transport is that it takes place in a confined environment; Besides several types of motors are involved, that move in opposite directions. It is a challenge to understand how this bidirectional transport is organized. We review several features that could contribute to the efficiency of bidirectional transport in the axon, including in particular the role of motor-motor interactions and of the dynamics of the underlying microtubule network. Finally, we also discuss some open questions that may be relevant for future research in this field.

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Section: I E W Smentioning

confidence: 99%

“…However, if by chance this protecting GTP cap disappears, the remaining part of the microtubule can depolymerize very rapidly: it is the aforementioned catastrophe. Depolymerization may end when an island of GTP (a GTP remnant inside the MT) is reached [95], inducing rescue, and a new episode of growth.…”

Section: I E W Smentioning

confidence: 99%

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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“…Dans d'autres études, nous avons montré que les méthodes de crible par la technique du phage display permettent de sélectionner des scFv dits conformationnels ne détectant que certains états tridimensionnels de la protéine ciblée. Nous avons ainsi réussi à produire des anticorps dirigés contre les formes liées au GTP de Rab6 [11] ou de la tubuline [12]. Ces anticorps utilisés comme intrabodies nous ont permis d'obtenir des résultats originaux : nous avons ainsi mis en évidence la dynamique endogène de cette protéine [11] et de l'anti-tubuline et avons proposé un nouveau modèle expliquant la dynamique instable des microtubules [12].…”

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“…Nous avons ainsi réussi à produire des anticorps dirigés contre les formes liées au GTP de Rab6 [11] ou de la tubuline [12]. Ces anticorps utilisés comme intrabodies nous ont permis d'obtenir des résultats originaux : nous avons ainsi mis en évidence la dynamique endogène de cette protéine [11] et de l'anti-tubuline et avons proposé un nouveau modèle expliquant la dynamique instable des microtubules [12]. La sélection d'intrabodies a aussi été réalisée en utilisant des anticorps de lamas qui semblent montrer une meilleure résistance à la réduction cytoplasmique [13] (➜).…”

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Utilisation desintrabodies: de l’étude des protéines intracellulaires à l’immunisation thérapeutique

Moutel

Perez

2009

Med Sci (Paris)

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“…MT assembly consumes energy since tubulins bound to GTP are added to MT ends during polymerization. GTP is then hydrolyzed to GDP, and most of the MT, except its tip and possibly very small segments along the MT wall, is composed of tubulins bound to GDP [Howard and Hyman, 2003;Dimitrov et al, 2008;van der Vaart et al, 2009]. As a MT depolymerizes, the released tubulin dimers exchange their bound GDP for GTP.…”

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Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

et al. 2012

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Microtubules (MTs) or their subunits, tubulin dimers, interact with multiple components that contribute to intracellular metabolic pathways. MTs are required for insulin-dependent transport of glucose transporter 4 to the plasma membrane, they bind most glycolytic enzymes and are required for translation of the mRNA encoding hypoxia inducible factor-1a. Tubulin dimers bind the voltage-dependent anion channel of the mitochondrial outer membrane; this channel functions in metabolite transport in and out of mitochondria. We hypothesize that tubulin partitioning between dimer and polymer pools regulates multiple steps in metabolism, where metabolic output is greatest when both tubulin dimers and MT polymers are present and reduced by drug treatments that disrupt this normal balance. Experimental evidence from these drug-induced changes in tubulin dimer/polymer partitioning supports our model for several metabolic steps. Signal transduction pathways that stabilize or destabilize MTs can shift the normal ratio between unpolymerized and polymerized tubulin dimers, and one downstream consequence of this shift in tubulin partitioning could be a change in metabolic output. V C 2012 Wiley Periodicals, Inc Key Words: glycolysis, oxidative phosphorylation, glucose transport, voltage-dependent anion channel, tubulin IntroductionT he microtubule (MT) cytoskeleton has well-characterized roles in cell polarity, motility, mitosis, and vesicle traffic. The dynamic turnover of MTs is critical to most of these processes, allowing the cell to reorganize an array of MTs rapidly for specific functions. Here we posit an additional role for MTs in regulating metabolic processes and propose that metabolism is greatest when both MTs and their tubulin subunits are present in cells. Disruption of this normal balance, to either inhibit or promote MT polymerization, is expected to decrease metabolic output. Our hypothesis predicts that chemotherapies that stabilize or destabilize MTs will significantly impact metabolic pathways and reduce ATP levels. Importantly, even a small decrease in ATP production can slow cell proliferation. For example, a 19% decrease in ATP production was sufficient to induce senescence in mouse embryo fibroblasts [Kondoh et al., 2005], indicating that even a relatively small contribution of the MT cytoskeleton to metabolic output could have a significant impact on cell fate.The metabolic components and pathways we consider here include glucose transporters (GLUTs), glycolysis, the pentose phosphate pathway (PPP), and mitochondrial oxidative phosphorylation. Glucose enters cells through glucose transporters called GLUTs; the concentration of GLUTs at the plasma membrane can be regulated by insulin and requires trafficking of GLUT-containing vesicles along MTs to reach the plasma membrane. Within the cytoplasm, glucose is broken down to pyruvate during glycolysis, yielding ATP and NADH. Several intermediate products of glucose breakdown, including glucose-6-phosphate (G6P) and glyceraldehyde-3-phosphate (GAP), can also ...

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Detection of GTP-Tubulin Conformation in Vivo Reveals a Role for GTP Remnants in Microtubule Rescues

Cited by 244 publications

References 19 publications

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

Utilisation desintrabodies: de l’étude des protéines intracellulaires à l’immunisation thérapeutique

Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

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