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Cold Spring Harbor Perspectives in... Jun 2018Microtubules act as "railways" for motor-driven intracellular transport, interact with accessory proteins to assemble into larger structures such as the mitotic spindle,... (Review)
Review
Microtubules act as "railways" for motor-driven intracellular transport, interact with accessory proteins to assemble into larger structures such as the mitotic spindle, and provide an organizational framework to the rest of the cell. Key to these functions is the fact that microtubules are "dynamic." As with actin, the polymer dynamics are driven by nucleotide hydrolysis and influenced by a host of specialized regulatory proteins, including microtubule-associated proteins. However, microtubule turnover involves a surprising behavior-termed dynamic instability-in which individual polymers switch stochastically between growth and depolymerization. Dynamic instability allows microtubules to explore intracellular space and remodel in response to intracellular and extracellular cues. Here, we review how such instability is central to the assembly of many microtubule-based structures and to the robust functioning of the microtubule cytoskeleton.
Topics: Animals; Microtubule-Associated Proteins; Microtubules; Mitosis; Models, Molecular; Protein Conformation
PubMed: 29858272
DOI: 10.1101/cshperspect.a022608 -
Current Opinion in Cell Biology Feb 2021The stochastic switching between microtubule growth and shrinkage is a fascinating and unique process in the regulation of the cytoskeleton. To understand it, almost all... (Review)
Review
The stochastic switching between microtubule growth and shrinkage is a fascinating and unique process in the regulation of the cytoskeleton. To understand it, almost all attention has been focused on the microtubule ends. However, recent research has revived the idea that tubulin dimers can also be exchanged in protofilaments along the microtubule shaft, thus repairing the microtubule and protecting it from disassembly. Here, we review the research describing this phenomenon, the mechanisms regulating the removal and insertion of tubulin dimers, as well as the potential implications for key functions of the microtubule network, such as intracellular transport and cell polarization.
Topics: Animals; Biomechanical Phenomena; Cell Physiological Phenomena; Cytoskeleton; Humans; Microtubules; Tubulin
PubMed: 33217636
DOI: 10.1016/j.ceb.2020.10.012 -
Nature Reviews. Molecular Cell Biology Dec 2021Microtubule dynamics and their control are essential for the normal function and division of all eukaryotic cells. This plethora of functions is, in large part,... (Review)
Review
Microtubule dynamics and their control are essential for the normal function and division of all eukaryotic cells. This plethora of functions is, in large part, supported by dynamic microtubule tips, which can bind to various intracellular targets, generate mechanical forces and couple with actin microfilaments. Here, we review progress in the understanding of microtubule assembly and dynamics, focusing on new information about the structure of microtubule tips. First, we discuss evidence for the widely accepted GTP cap model of microtubule dynamics. Next, we address microtubule dynamic instability in the context of structural information about assembly intermediates at microtubule tips. Three currently discussed models of microtubule assembly and dynamics are reviewed. These are considered in the context of established facts and recent data, which suggest that some long-held views must be re-evaluated. Finally, we review structural observations about the tips of microtubules in cells and describe their implications for understanding the mechanisms of microtubule regulation by associated proteins, by mechanical forces and by microtubule-targeting drugs, prominently including cancer chemotherapeutics.
Topics: Actin Cytoskeleton; Animals; Biomechanical Phenomena; Guanosine Triphosphate; Humans; Microtubule-Associated Proteins; Microtubules; Models, Biological; Tubulin; Tubulin Modulators
PubMed: 34408299
DOI: 10.1038/s41580-021-00399-x -
Annual Review of Cell and Developmental... 1997The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can... (Review)
Review
The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can change rapidly in response to cellular needs and, in some cases, to perform mechanical work. Microtubules utilize the energy of GTP hydrolysis to fuel a unique polymerization mechanism termed dynamic instability. In this review, we first describe progress toward understanding the mechanism of dynamic instability of pure tubulin and then discuss the function and regulation of microtubule dynamic instability in living cells.
Topics: Animals; Dimerization; Guanosine Triphosphate; Microtubule-Associated Proteins; Microtubules; Polymers; Thermodynamics; Tubulin
PubMed: 9442869
DOI: 10.1146/annurev.cellbio.13.1.83 -
Drug Discovery Today Feb 2021The association of microtubule (MT) breakdown with neurodegeneration and neurotoxicity has provided an emerging therapeutic approach for neurodegenerative diseases.... (Review)
Review
The association of microtubule (MT) breakdown with neurodegeneration and neurotoxicity has provided an emerging therapeutic approach for neurodegenerative diseases. Tubulin binders are able to modulate MT dynamics and, as a result, are of particular interest both as potential therapeutics and experimental tools used to validate this strategy. Here, we provide a comprehensive overview of current knowledge and recent advancements regarding MT-targeting approaches for neurodegeneration and evaluate the potential application of MT-targeting agents (MTAs) based on available preclinical and clinical data.
Topics: Animals; Drug Development; Humans; Microtubules; Molecular Targeted Therapy; Neurodegenerative Diseases
PubMed: 33279455
DOI: 10.1016/j.drudis.2020.11.033 -
Neuroscience Letters Jun 2021Neurons are the perfect example of cells where microtubules are essential to achieve an extraordinary degree of morphological and functional complexity. Different... (Review)
Review
Neurons are the perfect example of cells where microtubules are essential to achieve an extraordinary degree of morphological and functional complexity. Different tubulin isoforms and associated post-translational modifications are the basis to establish the diversity in biochemical and biophysical properties of microtubules including their stability and the control of intracellular transport. Acetylation is one of the key tubulin modifications and it can influence important structural, mechanical and biological traits of the microtubule network. Here, we present the emerging evidence for the essential role of microtubule acetylation in the control of neuronal and glial function in healthy and degenerative conditions. In particular, we discuss the pathogenic role of tubulin acetylation in neurodegenerative disorders and focus on Parkinson's disease. We also provide a critical analysis about the possibility to target tubulin acetylation as a novel therapeutic intervention for neuroprotective strategies.
Topics: Acetylation; Animals; Humans; Microtubules; Neurodegenerative Diseases; Neurons
PubMed: 33878428
DOI: 10.1016/j.neulet.2021.135900 -
Essays in Biochemistry Dec 2018The development of cryo-electron microscopy (cryo-EM) allowed microtubules to be captured in their solution-like state, enabling decades of insight into their dynamic... (Review)
Review
The development of cryo-electron microscopy (cryo-EM) allowed microtubules to be captured in their solution-like state, enabling decades of insight into their dynamic mechanisms and interactions with binding partners. Cryo-EM micrographs provide 2D visualization of microtubules, and these 2D images can also be used to reconstruct the 3D structure of the polymer and any associated binding partners. In this way, the binding sites for numerous components of the microtubule cytoskeleton-including motor domains from many kinesin motors, and the microtubule-binding domains of dynein motors and an expanding collection of microtubule associated proteins-have been determined. The effects of various microtubule-binding drugs have also been studied. High-resolution cryo-EM structures have also been used to probe the molecular basis of microtubule dynamic instability, driven by the GTPase activity of β-tubulin. These studies have shown the conformational changes in lattice-confined tubulin dimers in response to steps in the tubulin GTPase cycle, most notably lattice compaction at the longitudinal inter-dimer interface. Although work is ongoing to define a complete structural model of dynamic instability, attention has focused on the role of gradual destabilization of lateral contacts between tubulin protofilaments, particularly at the microtubule seam. Furthermore, lower resolution cryo-electron tomography 3D structures are shedding light on the heterogeneity of microtubule ends and how their 3D organization contributes to dynamic instability. The snapshots of these polymers captured using cryo-EM will continue to provide critical insights into their dynamics, interactions with cellular components, and the way microtubules contribute to cellular functions in diverse physiological contexts.
Topics: Animals; Binding Sites; Cryoelectron Microscopy; Humans; Microtubule-Associated Proteins; Microtubules; Models, Molecular; Protein Conformation
PubMed: 30315096
DOI: 10.1042/EBC20180031 -
Molecular Neurobiology Nov 2017Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of... (Review)
Review
Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of specification and polarization of various cell types, including neurons. Although microtubules could have a role in the death of many cells and tissues, the microtubule-based degenerative mechanisms have been poorly investigated; nevertheless, during the last two decades, many clues have been accumulated suggesting the importance of the microtubule system during neurodegeneration. Thus, the aim of this review is to analyse how the changes of the microtubule cytoskeleton, in terms of organization and dynamics, as well as the failure of the microtubule-dependent neuronal processes, as axonal transport, may play a pivotal role in the chain of events leading to Parkinson's disease. Last but not least, since disease-modifying or neuroprotective strategies are a clinical priority in Parkinson's disease, we will also present the hints about the concrete possibility of a microtubule-targeted therapy, which would have the potentiality to block the running degenerative events and to prompt the regeneration of the lost tissues.
Topics: Animals; Humans; Microtubule-Associated Proteins; Microtubules; Parkinson Disease; Protein Stability; Protein Structure, Secondary
PubMed: 27757833
DOI: 10.1007/s12035-016-0188-5 -
Current Opinion in Cell Biology Feb 2013Microtubules are long cylindrical polymers composed of tubulin subunits. In cells, microtubules play an essential role in architecture and motility. For example,... (Review)
Review
Microtubules are long cylindrical polymers composed of tubulin subunits. In cells, microtubules play an essential role in architecture and motility. For example, microtubules give shape to cells, serve as intracellular transport tracks, and act as key elements in important cellular structures such as axonemes and mitotic spindles. To accomplish these varied functions, networks of microtubules in cells are very dynamic, continuously remodeling through stochastic length fluctuations at the ends of individual microtubules. The dynamic behavior at the end of an individual microtubule is termed 'dynamic instability'. This behavior manifests itself by periods of persistent microtubule growth interrupted by occasional switching to rapid shrinkage (called microtubule 'catastrophe'), and then by switching back from shrinkage to growth (called microtubule 'rescue'). In this review, we summarize recent findings which provide new insights into the mechanisms of microtubule catastrophe and rescue, and discuss the impact of these findings in regards to the role of microtubule dynamics inside of cells.
Topics: Biomechanical Phenomena; Cellular Senescence; Guanosine Triphosphate; Humans; Microtubules; Spindle Apparatus; Tubulin
PubMed: 23092753
DOI: 10.1016/j.ceb.2012.09.006 -
Cell Motility and the Cytoskeleton 1992
Review
Topics: Animals; Biological Clocks; Hydrolysis; Microtubules; Models, Biological; Nucleotides
PubMed: 1516147
DOI: 10.1002/cm.970220403