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Journal of Nanobiotechnology Dec 2020Microtubules and carbon nanotubes (CNTs), and more particularly multi-walled CNTs (MWCNTs), share many mechanical and morphological similarities that prompt their... (Review)
Review
Microtubules and carbon nanotubes (CNTs), and more particularly multi-walled CNTs (MWCNTs), share many mechanical and morphological similarities that prompt their association into biosynthetic tubulin filaments both, in vitro and in vivo. Unlike CNTs, microtubules are highly dynamic protein polymers that, upon interaction with these nanomaterials, display enhanced stability that has critical consequences at the cellular level. Among others, CNTs prompt ectopic (acentrosomal) microtubule nucleation and the disassembly of the centrosome, causing a dramatic cytoskeletal reorganization. These changes in the microtubule pattern trigger the generation of ineffective biomechanical forces that result in migration defects, and ultimately in spindle-assembly checkpoint (SAC) blockage and apoptosis. In this review, we describe the molecular mechanism involved in the intrinsic interference of CNTs with the microtubule dynamics and illustrate the consequences of this effect on cell biomechanics. We also discuss the potential application of these synthetic microtubule-stabilizing agents as synergetic agents to boost the effect of classical chemotherapy that includes spindle poisons (i.e. paclitaxel) or DNA interfering agents (5-fluorouracil)-, and list some of the advantages of the use of MWCNTs as adjuvant agents in preventing cell resistance to chemotherapy.
Topics: Apoptosis; Cell Cycle; Centrosome; Cytoskeleton; Humans; Microtubules; Nanotubes, Carbon; Neoplasms; Paclitaxel; Phenotype; Tubulin
PubMed: 33317574
DOI: 10.1186/s12951-020-00742-y -
Scientific Reports Aug 2019Tau is a microtubule-associated protein that regulates axonal transport, stabilizes and spatially organizes microtubules in parallel networks. The Tau-microtubule pair...
Tau is a microtubule-associated protein that regulates axonal transport, stabilizes and spatially organizes microtubules in parallel networks. The Tau-microtubule pair is crucial for maintaining the architecture and integrity of axons. Therefore, it is essential to understand how these two entities interact to ensure and modulate the normal axonal functions. Based on evidence from several published experiments, we have developed a two-dimensional model that describes the interaction between a population of Tau proteins and a stabilized microtubule at the scale of the tubulin dimers (binding sites) as an adsorption-desorption dynamical process in which Tau can bind on the microtubule outer surface via two distinct modes: a longitudinal (along a protofilament) and lateral (across adjacent protofilaments) modes. Such a process yields a dynamical distribution of Tau molecules on the microtubule surface referred to as microtubule decoration that we have characterized at the equilibrium using two observables: the total microtubule surface coverage with Tau's and the distribution of nearest neighbors Tau's. Using both analytical and numerical approaches, we have derived expressions and computed these observables as a function of key parameters controlling the binding reaction: the stoichiometries of the Taus in the two binding modes, the associated dissociation constants and the ratio of the Tau concentration to that of microtubule tubulin dimers.
Topics: Humans; Microtubules; Models, Chemical; Tubulin; tau Proteins
PubMed: 31462746
DOI: 10.1038/s41598-019-48790-1 -
ELife Jun 2021The organization of micron-sized, multi-microtubule arrays from individual microtubules is essential for diverse cellular functions. The microtubule polymer is largely... (Review)
Review
The organization of micron-sized, multi-microtubule arrays from individual microtubules is essential for diverse cellular functions. The microtubule polymer is largely viewed as a passive building block during the organization process. An exception is the 'tubulin code' where alterations to tubulin at the amino acid level can influence the activity of microtubule-associated proteins. Recent studies reveal that micron-scale geometrical features of individual microtubules and polymer networks, such as microtubule length, overlap length, contact angle, and lattice defects, can also regulate the activity of microtubule-associated proteins and modulate polymer dynamics. We discuss how the interplay between such geometrical properties of the microtubule lattice and the activity of associated proteins direct multiple aspects of array organization, from microtubule nucleation and coalignment to specification of array dimensions and remodeling of dynamic networks. The mechanisms reviewed here highlight micron-sized features of microtubules as critical parameters to be routinely investigated in the study of microtubule self-organization.
Topics: Biological Phenomena; Humans; Interphase; Microtubule-Associated Proteins; Microtubules; Particle Size; Polymers; Tubulin
PubMed: 34114950
DOI: 10.7554/eLife.63880 -
Developmental Neurobiology Apr 2015Synaptic plasticity is a hallmark of the nervous system and is thought to be integral to higher brain functions such as learning and memory. Calcium, acting as a second... (Review)
Review
Synaptic plasticity is a hallmark of the nervous system and is thought to be integral to higher brain functions such as learning and memory. Calcium, acting as a second messenger, and the calcium/calmodulin dependent kinase CaMKII are key regulators of neuronal plasticity. Given the importance of the actin and microtubule (MT) cytoskeleton in dendritic spine morphology, composition and plasticity, it is not surprising that many regulators of these cytoskeletal elements are downstream of the CaMKII pathway. In this review, we discuss the emerging role of calcium and CaMKII in the regulation of MTs and cargo unloading during synaptic plasticity.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cytoskeleton; Microtubules; Signal Transduction
PubMed: 25156276
DOI: 10.1002/dneu.22227 -
Trends in Biochemical Sciences Dec 2015The motile and sensory functions of cilia and flagella are indispensable for human health. Cilia assembly requires a dedicated protein shuttle, intraflagellar transport... (Review)
Review
The motile and sensory functions of cilia and flagella are indispensable for human health. Cilia assembly requires a dedicated protein shuttle, intraflagellar transport (IFT), a bidirectional motility of multi-megadalton protein arrays along ciliary microtubules. IFT functions as a protein carrier delivering hundreds of distinct proteins into growing cilia. IFT-based protein import and export continue in fully grown cilia and are required for ciliary maintenance and sensing. Large ciliary building blocks might depend on IFT to move through the transition zone, which functions as a ciliary gate. Smaller, freely diffusing proteins, such as tubulin, depend on IFT to be concentrated or removed from cilia. As I discuss here, recent work provides insights into how IFT interacts with its cargoes and how the transport is regulated.
Topics: Animals; Cilia; Humans; Microtubules; Protein Transport; Proteins
PubMed: 26498262
DOI: 10.1016/j.tibs.2015.09.003 -
Scientific Reports Mar 2015Several strategies for controlling microtubule patterns are developed because of the rigidity determined from the molecular structure and the geometrical structure. In...
Several strategies for controlling microtubule patterns are developed because of the rigidity determined from the molecular structure and the geometrical structure. In contrast to the patterns in co-operation with motor proteins or associated proteins, microtubules have a huge potential for patterns via their intrinsic flexural rigidity. We discover that a microtubule teardrop pattern emerges via self-assembly under hydrodynamic flow from the parallel bundles without motor proteins. In the growth process, the bundles ultimately bend according to the critical bending curvature. Such protein pattern formation utilizing the intrinsic flexural rigidity will provide broad understandings of self-assembly of rigid rods, not only in biomolecules, but also in supramolecules.
Topics: Algorithms; Animals; Microscopy, Fluorescence; Microtubules; Models, Theoretical; Rhodamines; Tubulin
PubMed: 25823414
DOI: 10.1038/srep09581 -
Analytical Cellular Pathology... 2015Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In... (Review)
Review
Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.
Topics: Antineoplastic Agents; Humans; Microtubules; Neoplasms
PubMed: 26484003
DOI: 10.1155/2015/690916 -
Molecular Biology of the Cell Jul 2022The centriole is a minute cylindrical organelle present in a wide range of eukaryotic species. Most centrioles have a signature ninefold radial symmetry of microtubules...
The centriole is a minute cylindrical organelle present in a wide range of eukaryotic species. Most centrioles have a signature ninefold radial symmetry of microtubules that is imparted to the axonemes of the cilia and flagella they template, with nine centriolar microtubule doublets growing into nine axonemal microtubule doublets. There are exceptions to the ninefold symmetrical arrangement of axonemal microtubules in some species, with lower or higher fold symmetries. In the few cases where this has been examined, such alterations in axonemal symmetries are grounded in similar alterations in centriolar symmetries. Here, we examine the question of microtubule number continuity between centriole and axoneme in flagellated gametes of the gregarine , which have been reported to exhibit a sixfold radial symmetry of axonemal microtubules. We used time-lapse differential interference microscopy to identify the stage at which flagellated gametes are present. Thereafter, using electron microscopy and ultrastructure-expansion microscopy coupled to stimulated emission depletion superresolution imaging, we uncover that a six- or fivefold radial symmetry in the axoneme is accompanied by an eightfold radial symmetry in the centriole. We conclude that the transition between centriolar and axonemal microtubules can be characterized by unexpected plasticity.
Topics: Apicomplexa; Axoneme; Centrioles; Cilia; Flagella; Microtubules
PubMed: 35544302
DOI: 10.1091/mbc.E22-04-0123 -
Acta Crystallographica. Section D,... Apr 2024The axoneme, a microtubule-based array at the center of every cilium, has been the subject of structural investigations for decades, but only recent advances in cryo-EM... (Review)
Review
The axoneme, a microtubule-based array at the center of every cilium, has been the subject of structural investigations for decades, but only recent advances in cryo-EM and cryo-ET have allowed a molecular-level interpretation of the entire complex to be achieved. The unique properties of the nine doublet microtubules and central pair of singlet microtubules that form the axoneme, including the highly decorated tubulin lattice and the docking of massive axonemal complexes, provide opportunities and challenges for sample preparation, 3D reconstruction and atomic modeling. Here, the approaches used for cryo-EM and cryo-ET of axonemes are reviewed, while highlighting the unique opportunities provided by the latest generation of AI-guided tools that are transforming structural biology.
Topics: Axoneme; Cilia; Microtubules; Molecular Biology
PubMed: 38451206
DOI: 10.1107/S2059798324001815 -
Cell Structure and Function Oct 2016Polarized epithelial cells contain a characteristic array of microtubules in which non-centrosomal microtubules are aligned along the apical-to-basal axis of the cell... (Review)
Review
Polarized epithelial cells contain a characteristic array of microtubules in which non-centrosomal microtubules are aligned along the apical-to-basal axis of the cell with their minus ends oriented towards the apical pole. Although this unique orientation of microtubules was discovered in the late 1980s, how this orientation is established remains unresolved partly because of limited information about molecular factors that regulate the minus ends of non-centrosomal microtubules. Recent studies, however, identified novel minus end-associated proteins, revealing mechanisms by which the polarized arrays of microtubules are established in epithelial cells. These studies have also demonstrated the importance of apico-basally orientated microtubules in intra-structural organization of cells. This review focuses on recent progress of our understanding of the molecular basis for epithelium-specific microtubule assembly and function.
Topics: Animals; Epithelium; Intercellular Junctions; Microtubule-Associated Proteins; Microtubules; Models, Molecular
PubMed: 27615606
DOI: 10.1247/csf.16015