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Microtubules are a component of the cytoskeleton, found throughout the cytoplasm. These tubular polymers of tubulin can grow as long as 25 micrometres and are highly dynamic. The outer diameter of microtubule is about 25 nm while the inner diameter is about 12 nm. They are found in eukaryotic cells and are formed by the polymerization of a dimer of two globular proteins, alpha and beta tubulin.
Microtubules are important in a number of cellular processes. They are involved in maintaining cell structure and together with microfilaments and intermediate filaments, they form the cytoskeleton. They also make up the internal structure of cilia and flagella.They provide platforms for intracellular transport and are involved in a variety of cellular processes that involve the movement of secretory vesicles and organelles as well as the intracellular transport of substances (see entries for dynein and kinesin).[1] They are also involved in cell division (mitosis and meiosis) including the formation of mitotic spindles, which is the process by which eukaryotic cells separate their chromatids during cell division.
Microtubules are nucleated and organized in microtubule organizing centres (MTOCs), such as the centrosome or the basal bodies found in cilia and flagella. These MTOCs may or may not possess centrioles.
There are many proteins that bind to microtubules, including motor proteins such as kinesin and dynein, severing proteins like katanin, and other proteins important for regulating microtubule dynamics.[2]
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Microtubules are long, hollow cylinders made up of polymerised α- and β-tubulin dimers.[3]
The tubulin dimers polymerize end to end in protofilaments, which are the building block for the microtubule structure. Thirteen protofilaments associate laterally to form a single microtubule and this structure can then extend by the addition of more protofilaments. In order for polymerization to occur dimers must be present at a concentration above a specific minimum called the critical concentration, although the process is accelerated by the addition of nuclei, which are lengthened.
The lateral association of the protofilaments generates an imperfect helix with one turn of the helix containing 13 tubulin dimers, each from a different protofilament. The image at the top of this article illustrates a small section of a microtubule, a few αβ dimers in length. The number of protofilaments can vary; microtubules made up of 14 protofilaments have been seen in vitro.
Microtubules have a distinct polarity which is important for their biological function. Tubulin polymerizes end to end with the α-subunits of one tubulin dimer contacting the β-subunits of the next. Therefore, in a protofilament, one end will have the α-subunits exposed while the other end will have the β-subunits exposed. These ends are designated the (−) and (+) ends, respectively. The protofilaments bundle parallel to one another, so, in a microtubule, there is one end, the (+) end, with only β-subunits exposed, while the other end, the (−) end, has only α-subunits exposed. Elongation of microtubules typically only occurs from the (+) end.[4]
Microtubules are part of a structural network (the cytoskeleton) within the cell's cytoplasm. The primary role of the microtubule cytoskeleton is mechanical. However, in addition to structural support, microtubules also take part in many other processes. A microtubule is capable of growing and shrinking in order to generate force, and there are also motor proteins that allow organelles and other cellular factors to be carried along a microtubule. This combination of roles makes microtubules important for organizing cell layout.
Microtubules are typically nucleated and organized by dedicated organelles called microtubule-organizing centres (MTOCs). MTOCs associated with the base of a eukaryotic cilium or flagellum are typically termed basal bodies, otherwise they are called centrioles. In many cell types microtubules are primarily nucleated at MTOCs, however, there are also many exceptions to this rule.
Microtubules have a major structural role in eukaryotic cilia and flagella. Cilia and flagella are also notable in that they always extend directly from a MTOC, in this case termed the basal body. The action of motor proteins on the neighbouring microtubule strands which run along a cilia or flagellum allow the organelle to bend and generate force for swimming, moving extracellular material, and other roles.
Note that prokaryotes do not possess tubulin or microtubules. Prokaryote (both bacterial and archeal) flagella are entirely different in structure to eukaryotic flagella.
A notable structure involving microtubules is the mitotic spindle used by most eukaryotic cells to segregate their chromosomes correctly during cell division.
The process of mitosis is facilitated by a subgroup of microtubules known as astral microtubules, defined as a microtubule originating from the centrosome that does not connect to a kinetochore. Astral microtubules develop in the actin skeleton and interact with the cell cortex to aid in spindle orientation. They are organized into radial arrays around the centrosomes. The turnover rate of this population of microtubules is higher than that of any other population. Astral microtubules function in concert with specialized dynein motors, which are oriented with the light chain portion attached to the cell membrane and the dynamic portion attached to the microtubule. This allows for dynein contraction to pull the centrosome toward the cell membrane, thus assisting in cytokinesis.
Astral microtubules are not required for the progression of mitosis, but they are required to ensure the fidelity of the process; they are required for the correct positioning and orientation of the mitotic spindle apparatus. They are also involved in determination of cell division site based on the geometry and polarity of the cells. The maintenance of astral microtubules is dependent on the integrity of the centrosome. It is also dependent on several microtubule-associated proteins such as EB1 and Adenomatous Polyposis Coli (APC).
Cell division in a typical eukaryote finishes with the generation of a final cytoplasmic bridge between the two daughter cells termed the midbody. This structure is rich in microtubules and is built up of microtubules that originally made up part of the spindle.
Microtubules are often nucleated at a dedicated microtubule-organizing centre. Contained within the MTOC is another type of tubulin, γ-tubulin, which is distinct from the α- and β-subunits, which compose the microtubules themselves. The γ-tubulin combines with several other associated proteins to form a circular structure known as the "γ-tubulin ring complex" (γ-TuRC). This complex acts as a scaffold for α/β-tubulin dimers to begin polymerization; it acts as a cap of the (−) end while microtubule growth continues away from the MTOC in the (+) direction.[5]
Some cell types, such as plant cells, do not contain MTOCs. In these cells, microtubules are nucleated from discrete sites in the cytoplasm. Other cell types, such as trypanosomatid parasites, have a MTOC but it is permanently found at the base of a flagellum. Nucleation of microtubules for structural roles and for generation of the mitotic spindle is not from a canonical centriole-like MTOC. The regulation of the microtubule cytoskeleton in these cells is an intense area of study.
Dynamic instability refers to the coexistence of assembly and disassembly at the (+) end of a microtubule. The microtubule can dynamically switch between growing and shrinking phases in this region.[6] During polymerization, both the α- and β-subunits of the tubulin dimer are bound to a molecule of GTP.[3] The GTP bound to α-tubulin is stable and it plays a structural function in this bound state. However, the GTP bound to β-tubulin may be hydrolyzed to GDP shortly after assembly resulting in the addition of new dimers. The kinetics of GDP-tubulin are different from those of GTP-tubulin as GDP-tubulin is prone to depolymerization.[7] A GDP-bound tubulin subunit at the tip of a microtubule will fall off, although a GDP-bound tubulin in the middle of a microtubule cannot spontaneously pop out. Since tubulin adds onto the end of the microtubule only in the GTP-bound state, there is a cap of GTP-bound tubulin at the tip of the microtubule, protecting it from disassembly. When hydrolysis catches up to the tip of the microtubule, it begins a rapid depolymerization and shrinkage. This switch from growth to shrinking is called a catastrophe. GTP-bound tubulin can begin adding to the tip of the microtubule again, providing a new cap and protecting the microtubule from shrinking. This is referred to as "rescue".[8]
The process of adding or removing monomers depends on the concentration of αβ-tubulin dimers in solution in relation to the critical concentration (Cc), which is the equilibrium constant for the dissociation of the dimers at the end of the microtubule.
The microtubule can therefore grow at both ends or only at one, depending on the concentrations of αβ-tubulin dimers. The interaction of the (-) end with MTOC will greatly decrease its activity.
These characteristics are derived from the existence of the microtubule’s dynamic instability, which means that in the same cell some microtubules are depolymerizing (catastrophe) and others are polymerizing (recovery).
“In vivo” microtubule dynamics vary considerably. Assembly, disassembly, and catastrophe rates depend on which microtubule-associated proteins (MAPs) are present. MAPs are classified by their molecular weight into two groups:
They are also called τ(tau) proteins. They line the microtubule and form links with adjacent microtubules.
There are four known types of the heavier molecular weight MAPs: MAP-1, MAP-2, MAP-3 and MAP-4 A MAP-1 protein is composed of at least three different proteins: A, B and C. The C protein plays an important role in the retrograde transport of vesicles and is known as cytoplasmic dynein.
MAP-2 proteins are located in the dendrites and in the body of neurons, where they bind with other filaments.
The MAP-4 proteins are found in the majority of cells and they stabilize the microtubules.
A great number of drugs are able to bond with tubulin and modify its activation state. This will have the effect of interfering with microtubule dynamics. These drugs can have an effect at intracellular concentrations much lower that that of tubulin. This interference with microtubule dynamics can have the effect of stopping a cell’s cell cycle and can lead to programmed cell death or apoptosis. The compounds that modify tubulin’s activity can be divided into two general groups: polymerization inhibitors, such as colchicine and depolymerization inhibitors.
The drugs that can alter microtubule dynamics include:
In addition to movement generated by the dynamic instability of the microtubule itself, the fibres are substrates along which motor proteins can move. Some proteins take advantage of the hydrolysis of ATP in order to generate mechanical energy and move substances along the microtubules. The major microtubule motor proteins are kinesin, which moves toward the (+) end of the microtubule, and dynein, which moves toward the (−) end.
Some viruses (including retroviruses, herpesviruses, parvoviruses, and adenoviruses) that require access to the nucleus to replicate their genomes attach to the motor proteins (dynein), which transport them at 1-4 μm/s to the centrosome, near the nucleus.
Microtubules play a part in biological processes in addition to their structural role as a component of the cytoskeleton (along with actin and the intermediate filaments).
The cytoskeleton formed by microtubules is essential to the morphogenetic process of an organism’s development. For example, a network of whole, polarized microtubules is required to be present within the oocyte of Drosophila melanogaster during its embryogenesis in order to establish the axis of the egg. Signals sent between the follicular cells and the oocyte (such as factors similar to epidermal growth factor) cause the reorganization of the microtubules so that their (-) ends are located in the lower part of the oocyte, polarizing the structure and leading to the appearance of an anterior-posterior axis.[9] This involvement in the body’s architecture is also seen in mammals.[10]
Another area where microtubules are essential is the formation of the nervous system in higher vertebrates, where tubulin’s dynamics and those of the associated proteins (such as the MAPs) is finely controlled during the development of the brain's neuronal base.[11]
The cellular cytoskeleton is a dynamic element that functions on many different levels: in addition to giving it a particular form and supporting the transport of vesicles and organelles it can also influence gene expression. However, the signal transduction mechanisms involved in this communication are little understood. Notwithstanding this, the relationship between the drug-mediated depolymerization of microtubules and the specific expression of transcription factors has been described, which has provided information on the differential expression of the genes depending on the presence of these factors.[12] This communication between the cytoskeleton and the regulation of the cellular response is also related to the generation of growth factors: for example, this relation exists for connective tissue growth factor.[13]
This fact has a vital inconsistency in cancer treatments as paclitaxel (sold under the trademark taxol, a widely used antineoplastic drug) acts on cytoskeletal microtubules and it is their interaction with elements that regulate the cell cycle that provokes, in the presence of antineoplastic drugs, a series of cellular failures in the cancerous cells that lead to planned cell death or apoptosis.[14]
In their controversial Orch-OR theory of consciousness, Roger Penrose and Stuart Hameroff postulate that microtubules in neurons conduct quantum-level manipulations of matter, which produces consciousness, based partially on some observations of Gamma Synchrony that indicate that information may propagate through the brain much faster than a chemically mediated neural network would physically permit. Max Tegmark disputes the relevance of these observations, and the matter remains open to debate. David Chalmers argues that quantum theories of consciousness suffer from the same weakness as more conventional theories.[15] Just as he argues that there is no particular reason why particular macroscopic physical features in the brain should give rise to consciousness, he also thinks that there is no particular reason why a particular quantum feature, such as the electromagnetic field in the brain, should give rise to consciousness, either. While at least one researcher, Michael Persinger, claims otherwise, Jeffrey Gray states in his book Consciousness: Creeping up on the Hard Problem, that tests looking for the influence of electromagnetic fields on brain function have been universally negative in their result.[16]
Proteins in different cellular compartments and structures tagged with green fluorescent protein.
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