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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 -
Nature Reviews. Cardiology Jun 2022The microtubule network of cardiac muscle cells has unique architectural and biophysical features to accommodate the demands of the working heart. Advances in live-cell... (Review)
Review
The microtubule network of cardiac muscle cells has unique architectural and biophysical features to accommodate the demands of the working heart. Advances in live-cell imaging and in deciphering the 'tubulin code' have shone new light on this cytoskeletal network and its role in heart failure. Microtubule-based transport orchestrates the growth and maintenance of the contractile apparatus through spatiotemporal control of translation, while also organizing the specialized membrane systems required for excitation-contraction coupling. To withstand the high mechanical loads of the working heart, microtubules are post-translationally modified and physically reinforced. In response to stress to the myocardium, the microtubule network remodels, typically through densification, post-translational modification and stabilization. Under these conditions, physically reinforced microtubules resist the motion of the cardiomyocyte and increase myocardial stiffness. Accordingly, modified microtubules have emerged as a therapeutic target for reducing stiffness in heart failure. In this Review, we discuss the latest evidence on the contribution of microtubules to cardiac mechanics, the drivers of microtubule network remodelling in cardiac pathologies and the therapeutic potential of targeting cardiac microtubules in acquired heart diseases.
Topics: Cytoskeleton; Heart Failure; Humans; Microtubules; Myocytes, Cardiac; Tubulin
PubMed: 35440741
DOI: 10.1038/s41569-022-00692-y -
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 -
Current Biology : CB Feb 2015Microtubules are cytoskeletal filaments that are intrinsically polarized, with two structurally and functionally distinct ends, the plus end and the minus end. Over the... (Review)
Review
Microtubules are cytoskeletal filaments that are intrinsically polarized, with two structurally and functionally distinct ends, the plus end and the minus end. Over the last decade, numerous studies have shown that microtubule plus-end dynamics play an important role in many vital cellular processes and are controlled by numerous factors, such as microtubule plus-end-tracking proteins (+TIPs). In contrast, the cellular machinery that controls the behavior and organization of microtubule minus ends remains one of the least well-understood facets of the microtubule cytoskeleton. The recent characterization of the CAMSAP/Patronin/Nezha family members as specific 'minus-end-targeting proteins' ('-TIPs') has provided important new insights into the mechanisms governing minus-end dynamics. Here, we review the current state of knowledge on how microtubule minus ends are controlled and how minus-end regulators contribute to non-centrosomal microtubule organization and function during cell division, migration and differentiation.
Topics: Eukaryota; Microtubule-Associated Proteins; Microtubules; Protein Transport
PubMed: 25689915
DOI: 10.1016/j.cub.2014.12.027 -
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 -
Current Opinion in Cell Biology Oct 2019Microtubules play essential roles in cellular organization, cargo transport, and chromosome segregation during cell division. During mitosis microtubules form a... (Review)
Review
Microtubules play essential roles in cellular organization, cargo transport, and chromosome segregation during cell division. During mitosis microtubules form a macromolecular structure known as the mitotic spindle that is responsible for the accurate segregation of chromosomes between the two daughter cells. This is accomplished thanks to finely tuned control of microtubule dynamics. Even small changes in microtubule dynamics during spindle formation and/or operation may lead to chromosome mis-segregation, chromosome instability and aneuploidy. These three events are directly correlated with human diseases like cancer and developmental defects. Precise measurements of microtubule dynamics in the spindle will allow us to discover new molecules involved in regulating microtubule dynamics and enable a deeper understanding of the mechanisms that underlie mitosis and cancer emergence and development. Moreover, many chemotherapeutic agents for cancer treatment are targeted to microtubules, so continued investigation of their dynamics with utmost precision will facilitate the development of new drugs. Measuring microtubule dynamics in the spindle has been a difficult task until recently. With the development of new and gentler microscopic techniques, and new computer programs, we can perform better and more accurate measurements of microtubule dynamics during mitosis.
Topics: Animals; Chromosomal Instability; Chromosome Segregation; Humans; Microtubules; Mitosis; Models, Biological; Spindle Apparatus
PubMed: 31108428
DOI: 10.1016/j.ceb.2019.03.017 -
Advances in Parasitology 2020Giardia lamblia is a widespread parasitic protist with a complex MT cytoskeleton that is critical for motility, attachment, mitosis and cell division, and transitions... (Review)
Review
Giardia lamblia is a widespread parasitic protist with a complex MT cytoskeleton that is critical for motility, attachment, mitosis and cell division, and transitions between its two life cycle stages-the infectious cyst and flagellated trophozoite. Giardia trophozoites have both highly dynamic and highly stable MT organelles, including the ventral disc, eight flagella, the median body and the funis. The ventral disc, an elaborate MT organelle, is essential for the parasite's attachment to the intestinal villi to avoid peristalsis. Giardia's four flagellar pairs enable swimming motility and may also promote attachment. They are maintained at different equilibrium lengths and are distinguished by their long cytoplasmic regions and novel extra-axonemal structures. The functions of the median body and funis, MT organelles unique to Giardia, remain less understood. In addition to conserved MT-associated proteins, the genome is enriched in ankyrins, NEKs, and novel hypothetical proteins that also associate with the MT cytoskeleton. High-resolution ultrastructural imaging and a current inventory of more than 300 proteins associated with Giardia's MT cytoskeleton lay the groundwork for future mechanistic analyses of parasite attachment to the host, motility, cell division, and encystation/excystation. Giardia's unique MT organelles exemplify the capacity of MT polymers to generate intricate structures that are diverse in both form and function. Thus, beyond its relevance to pathogenesis, the study of Giardia's MT cytoskeleton informs basic cytoskeletal biology and cellular evolution. With the availability of new molecular genetic tools to disrupt gene function, we anticipate a new era of cytoskeletal discovery in Giardia.
Topics: Giardia; Microtubules; Organelles
PubMed: 32122531
DOI: 10.1016/bs.apar.2019.11.001 -
International Journal of Molecular... Jun 2022Microtubules are major components of the cytoskeleton that play important roles in cellular processes such as intracellular transport and cell division. In recent years,... (Review)
Review
Microtubules are major components of the cytoskeleton that play important roles in cellular processes such as intracellular transport and cell division. In recent years, it has become evident that microtubule networks play a role in genome maintenance during interphase. In this review, we highlight recent advances in understanding the role of microtubule dynamics in DNA damage response and repair. We first describe how DNA damage checkpoints regulate microtubule organization and stability. We then highlight how microtubule networks are involved in the nuclear remodeling following DNA damage, which leads to changes in chromosome organization. Lastly, we discuss how microtubule dynamics participate in the mobility of damaged DNA and promote consequent DNA repair. Together, the literature indicates the importance of microtubule dynamics in genome organization and stability during interphase.
Topics: Cell Nucleus; Centrosome; Cytoskeleton; DNA Damage; Interphase; Microtubules
PubMed: 35805981
DOI: 10.3390/ijms23136986 -
Biomolecules Mar 2019The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically... (Review)
Review
The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c.
Topics: Animals; Humans; Microtubule-Associated Proteins; Microtubules; tau Proteins
PubMed: 30884818
DOI: 10.3390/biom9030105 -
Current Opinion in Cell Biology Feb 2020Microtubules control cell architecture by serving as a scaffold for intracellular transport, signaling, and organelle positioning. Microtubules are intrinsically... (Review)
Review
Microtubules control cell architecture by serving as a scaffold for intracellular transport, signaling, and organelle positioning. Microtubules are intrinsically polarized, and their orientation, density, and post-translational modifications both respond and contribute to cell polarity. Animal cells that can rapidly reorient their polarity axis, such as fibroblasts, immune cells, and cancer cells, contain radially organized microtubule arrays anchored at the centrosome and the Golgi apparatus, whereas stably polarized cells often acquire non-centrosomal microtubule networks attached to the cell cortex, nucleus, or other structures. Microtubule density, longevity, and post-translational modifications strongly depend on the dynamics of their plus ends. Factors controlling microtubule plus-end dynamics are often part of cortical assemblies that integrate cytoskeletal organization, cell adhesion, and secretion and are subject to microtubule-dependent feedback regulation. Finally, microtubules can mechanically contribute to cell asymmetry by promoting cell elongation, a property that might be important for cells with dense microtubule arrays growing in soft environments.
Topics: Animals; Cell Polarity; Humans; Microtubules
PubMed: 31739264
DOI: 10.1016/j.ceb.2019.10.004