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{{short description|Polymer of tubulin that forms part of the cytoskeleton}}
[[File:Tubulin Infographic.jpg|alt=Tubulin and Microtubule Metrics Infographic|thumb|440x440px|Microtubule and tubulin metrics<ref>{{Cite web|url=https://puresoluble.com/digital-downloads/|title=Digital Downloads|website=PurSolutions|language=en-US|access-date=2020-02-20|archive-date=2022-09-29|archive-url=https://web.archive.org/web/20220929022306/https://puresoluble.com/digital-downloads/|url-status=live}}</ref>]]
'''Microtubules''' are [[polymer]]s of [[tubulin]] that form part of the [[cytoskeleton]] and provide structure and shape to [[
Microtubules
Microtubules are [[Microtubule nucleation|nucleated]] and organized by [[microtubule
There are many proteins that bind to microtubules, including the [[motor protein]]s [[
== History ==
Tubulin and microtubule-mediated processes, like cell locomotion, were seen by early microscopists, like [[Leeuwenhoek]] (1677). However, the fibrous nature of flagella and other structures were discovered two centuries later, with improved [[light microscope]]s, and confirmed in the 20th century with the [[electron microscope]] and biochemical studies.<ref>Wayne, R. 2009. ''[https://books.google.com/books?id=t_biw80LgjwC Plant Cell Biology: From Astronomy to Zoology] {{Webarchive|url=https://web.archive.org/web/20240221025111/https://books.google.com/books?id=t_biw80LgjwC |date=2024-02-21 }}''. Amsterdam: Elsevier/Academic Press, p. 165.</ref>
== Structure ==
[[File:Tubulin dimer 1JFF.png|thumb|Cartoon representation of the structure of α(yellow)/β(red)-tubulin heterodimer, GTP and GDP.<ref>{{cite journal | vauthors = Löwe J, Li H, Downing KH, Nogales E | title = Refined structure of alpha beta-tubulin at 3.5 A resolution | journal = Journal of Molecular Biology | volume = 313 | issue = 5 | pages = 1045–57 | date = November 2001 | pmid = 11700061 | doi = 10.1006/jmbi.2001.5077 | url = https://zenodo.org/record/1229896 | access-date = 2019-09-09 | archive-date = 2021-01-22 | archive-url = https://web.archive.org/web/20210122161041/https://zenodo.org/record/1229896 | url-status = live }}</ref>]]
In eukaryotes, microtubules are long, hollow cylinders made up of polymerised α- and β-[[tubulin]] [[protein dimer|dimers]].<ref name="weisenberg">{{cite journal | vauthors = Weisenberg RC | title = Microtubule formation in vitro in solutions containing low calcium concentrations | journal = Science | volume = 177 | issue = 4054 | pages = 1104–5 | date = September 1972 | pmid = 4626639 | doi = 10.1126/science.177.4054.1104 | bibcode = 1972Sci...177.1104W | s2cid = 34875893 }}</ref> The inner space of the hollow microtubule cylinders is referred to as the lumen. The α and β-tubulin subunits are identical at the amino acid level, and each have a molecular weight of approximately 50 kDa.<ref name = "desai">{{cite journal | vauthors = Desai A, Mitchison TJ | title = Microtubule polymerization dynamics | journal = Annual Review of Cell and Developmental Biology | volume = 13 | pages = 83–117 | year = 1997 | pmid = 9442869 | doi = 10.1146/annurev.cellbio.13.1.83 }}</ref>▼
▲In
These α/β-tubulin [[protein dimer|dimers]] [[polymerize]] end-to-end into linear protofilaments that associate laterally to form a single microtubule, which can then be extended by the addition of more α/β-tubulin dimers. Typically, microtubules are formed by the parallel association of thirteen protofilaments, although microtubules composed of fewer or more [[protofilament]]s have been observed in various species <ref>{{cite journal | vauthors = Chaaban S, Brouhard GJ | title = A microtubule bestiary: structural diversity in tubulin polymers | journal = Molecular Biology of the Cell | volume = 28 | issue = 22 | pages = 2924–31 | date = 2017 | pmid = 29084910 | doi = 10.1091/mbc.E16-05-0271 | pmc = 5662251}}</ref> as well as ''in vitro''.<ref>{{cite journal | vauthors = Chrétien D, Metoz F, Verde F, Karsenti E, Wade RH | title = Lattice defects in microtubules: protofilament numbers vary within individual microtubules | journal = Journal of Cell Biology | volume = 117 | issue = 5 | pages = 1031–40 | date = June 1992 | pmid = 1577866 | doi = 10.1083/jcb.117.5.1031 | pmc = 2289483}}</ref>▼
▲These α/β-tubulin [[protein dimer|dimers]] [[polymerize]] end-to-end into linear '''protofilaments''' that associate laterally to form a single microtubule, which can then be extended by the addition of more α/β-tubulin dimers. Typically, microtubules are formed by the parallel association of thirteen protofilaments, although microtubules composed of fewer or more
Microtubules have a distinct polarity that is critical for their biological function. Tubulin polymerizes end to end, with the β-subunits of one tubulin dimer contacting the α-subunits of the next dimer. 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 with the same polarity, 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. While microtubule elongation can occur at both the (+) and (−) ends, it is significantly more rapid at the (+) end.<ref>{{cite journal | vauthors = Walker RA, O'Brien ET, Pryer NK, Soboeiro MF, Voter WA, Erickson HP, Salmon ED | title = Dynamic instability of individual microtubules analyzed by video light microscopy: rate constants and transition frequencies | journal = The Journal of Cell Biology | volume = 107 | issue = 4 | pages = 1437–48 | date = October 1988 | pmid = 3170635 | pmc = 2115242 | doi = 10.1083/jcb.107.4.1437 | citeseerx = 10.1.1.525.507 }}</ref>
The lateral association of the protofilaments generates a pseudo-helical structure, with one turn of the helix containing 13 tubulin dimers, each from a different protofilament. In the most common "13-3" architecture, the 13th tubulin dimer interacts with the next tubulin dimer with a vertical offset of 3 tubulin monomers due to the helicity of the turn. There are other alternative architectures, such as 11-3, 12-3, 14-3, 15-4, or 16-4, that have been detected at a much lower occurrence.<ref>{{cite journal | vauthors = Sui H, Downing KH | title = Structural basis of interprotofilament interaction and lateral deformation of microtubules | journal = Structure | volume = 18 | issue = 8 | pages = 1022–31 | date = August 2010 | pmid = 20696402 | pmc = 2976607 | doi = 10.1016/j.str.2010.05.010 }}</ref> Microtubules can also morph into other forms such as helical filaments, which are observed in [[protist]] organisms like [[foraminifera]].<ref>{{cite journal | vauthors = Bassen DM, Hou Y, Bowser SS, Banavali NK | title = Maintenance of electrostatic stabilization in altered tubulin lateral contacts may facilitate formation of helical filaments in foraminifera | journal = Scientific Reports | volume = 6 |
The sequence and exact composition of molecules during microtubule formation can thus be summarised as follows: A β-tubulin connects in the context of a non-existent covalent bond with an α-tubulin, which in connected form are a heterodimer, since they consist of two different polypeptides (β-tubulin and α-tubulin). So after the heterodimers are formed, they join together to form long chains that rise figuratively in one direction (e.g. upwards). These heterodimers, which are connected in a certain direction, form protofilaments. These long chains (protofilaments) now gradually accumulate next to each other so that a tube-like structure is formed, which has a lumen typical of a tube. Accordingly, mostly 13 protofilaments form the outer wall of the microtubules. The heterodimers consist of a positive and negative end, with alpha-tubulin forming the negative end and beta-tubulin the positive end. Due to the fact that the heterodimers are stacked on top of each other, there is always a negative and positive end. Microtubules grow by an addition of heterodimers at the plus end.
Some species of ''[[Prosthecobacter]]'' also contain microtubules. The structure of these bacterial microtubules is similar to that of eukaryotic microtubules, consisting of a hollow tube of protofilaments assembled from heterodimers of bacterial tubulin A (BtubA) and bacterial tubulin B (BtubB). Both BtubA and BtubB share features of both α- and β-[[tubulin]]. Unlike eukaryotic microtubules, bacterial microtubules do not require chaperones to fold.<ref>{{cite journal | vauthors = Schlieper D, Oliva MA, Andreu JM, Löwe J | title = Structure of bacterial tubulin BtubA/B: evidence for horizontal gene transfer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 26 | pages = 9170–5 | date = June 2005 | pmid = 15967998 | pmc = 1166614 | doi = 10.1073/pnas.0502859102 | bibcode = 2005PNAS..102.9170S | doi-access = free }}</ref> In contrast to the 13 protofilaments of eukaryotic microtubules, bacterial microtubules comprise only five.<ref name="
==Intracellular organization==
Microtubules are part of the [[cytoskeleton]], a structural network within the cell's [[cytoplasm]]. The roles of the microtubule cytoskeleton include mechanical support, organization of the cytoplasm, transport, motility and chromosome segregation. In developing neurons microtubules are known as [[neurotubule]]s,<ref name="Webster">{{cite web |title=Medical Definition of Neurotubules |url=https://www.merriam-webster.com/medical/neurotubules |website=www.merriam-webster.com |language=en |access-date=2018-09-26 |archive-date=2018-09-27 |archive-url=https://web.archive.org/web/20180927050133/https://www.merriam-webster.com/medical/neurotubules |url-status=live }}</ref> and they can modulate the dynamics of [[actin]], another component of the cytoskeleton.<ref>{{cite journal | vauthors = Zhao B, Meka DP, Scharrenberg R, König T, Schwanke B, Kobler O, Windhorst S, Kreutz MR, Mikhaylova M, Calderon de Anda F | title = Microtubules Modulate F-actin Dynamics during Neuronal Polarization | journal = Scientific Reports | volume = 7 | issue = 1 |
The organization of microtubules in the cell is cell-type specific. In [[epithelia]], the minus-ends of the microtubule polymer are anchored near the site of cell-cell contact and organized along the apical-basal axis. After nucleation, the minus-ends are released and then re-anchored in the periphery by factors such as [[ninein]] and [[PLEKHA7]].<ref>{{cite journal | vauthors = Bartolini F, Gundersen GG | title = Generation of noncentrosomal microtubule arrays | journal = Journal of Cell Science | volume = 119 | issue = Pt 20 | pages = 4155–63 | date = October 2006 | pmid = 17038542 | doi = 10.1242/jcs.03227 | doi-access = free }}</ref> In this manner, they can facilitate the transport of proteins, vesicles and organelles along the apical-basal axis of the cell. In [[fibroblast]]s and other mesenchymal cell-types, microtubules are anchored at the centrosome and radiate with their plus-ends outwards towards the cell periphery (as shown in the first figure). In these cells, the microtubules play important roles in cell migration. Moreover, the polarity of microtubules is acted upon by motor proteins, which organize many components of the cell, including the [[endoplasmic reticulum]] and the [[Golgi apparatus]].
[[File:FluorescentCells.jpg|thumb|right|Components of the [[eukaryotic]] cytoskeleton. [[Actin filaments]] are shown in red, [[microtubules]] are in green, and the [[cell nucleus|nuclei]] are in blue. The
==Microtubule polymerization==
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{{main|Microtubule nucleation}}
Nucleation is the event that initiates the formation of microtubules from the tubulin dimer. Microtubules are typically [[nucleate]]d and organized by organelles called [[microtubule-organizing
The [[centrosome]] is the primary MTOC of most cell types.
Some cell types, such as plant cells, do not contain well defined 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. Here, nucleation of microtubules for structural roles and for generation of the mitotic spindle is not from a canonical centriole-like MTOC.
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===Polymerization===
Following the initial nucleation event, tubulin monomers must be added to the growing polymer. The process of adding or removing monomers depends on the concentration of αβ-tubulin dimers in solution in relation to the critical concentration, which is the steady state concentration of dimers at which there is no longer any net assembly or disassembly at the end of the microtubule. If the dimer concentration is greater than the critical concentration, the microtubule will polymerize and grow. If the concentration is less than the critical concentration, the length of the microtubule will decrease.<ref>{{cite book | vauthors = Alberts B, Johnson A, Lewis J,
==Microtubule dynamics==
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[[File:MicrotubuleDynamicInstability.ogv|thumb|Animation of the microtubule dynamic instability. Tubulin dimers bound to GTP (red) bind to the growing end of a microtubule and subsequently hydrolyze GTP into GDP (blue).]]
Dynamic instability refers to the coexistence of assembly and disassembly at the ends of a microtubule. The microtubule can dynamically switch between growing and shrinking phases in this region.<ref>{{Cite book |
==="Search and capture" model===
In 1986, [[Marc Kirschner]] and [[Tim Mitchison]] proposed that microtubules use their dynamic properties of growth and shrinkage at their plus ends to probe the three dimensional space of the cell. Plus ends that encounter kinetochores or sites of polarity become captured and no longer display growth or shrinkage. In contrast to normal dynamic microtubules, which have a half-life of 5–10 minutes, the captured microtubules can last for hours. This idea is commonly known as the "search and capture" model.<ref>{{cite journal | vauthors = Kirschner M, Mitchison T | title = Beyond self-assembly: from microtubules to morphogenesis | journal = Cell | volume = 45 | issue = 3 | pages = 329–42 | date = May 1986 | pmid = 3516413 | doi = 10.1016/0092-8674(86)90318-1 | s2cid = 36994346 }}</ref> Indeed, work since then has largely validated this idea. At the kinetochore, a variety of complexes have been shown to capture microtubule (+)-ends.<ref name="pmid18097444">{{cite journal | vauthors = Cheeseman IM, Desai A | title = Molecular architecture of the kinetochore-microtubule interface | journal = Nature Reviews. Molecular Cell Biology | volume = 9 | issue = 1 | pages = 33–46 | date = January 2008 | pmid = 18097444 | doi = 10.1038/nrm2310 | s2cid = 34121605 }}</ref> Moreover, a (+)-end capping activity for interphase microtubules has also been described.<ref name="pmid11058078">{{cite journal | vauthors = Infante AS, Stein MS, Zhai Y, Borisy GG, Gundersen GG | title = Detyrosinated (Glu) microtubules are stabilized by an ATP-sensitive plus-end cap | journal = Journal of Cell Science | volume = 113
==Regulation of microtubule dynamics==
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* [[Detyrosination]]: the removal of the C-terminal [[tyrosine]] from alpha-tubulin. This reaction exposes a [[glutamate]] at the new C-terminus. As a result, microtubules that accumulate this modification are often referred to as Glu-microtubules. Although the tubulin carboxypeptidase has yet to be identified, the [[tubulin—tyrosine ligase]] (TTL) is known.<ref name="pmid8093886">{{cite journal | vauthors = Ersfeld K, Wehland J, Plessmann U, Dodemont H, Gerke V, Weber K | title = Characterization of the tubulin-tyrosine ligase | journal = The Journal of Cell Biology | volume = 120 | issue = 3 | pages = 725–32 | date = February 1993 | pmid = 8093886 | pmc = 2119537 | doi = 10.1083/jcb.120.3.725 }}</ref>
* Delta2: the removal of the last two residues from the C-terminus of alpha-tubulin.<ref name="pmid1931974">{{cite journal | vauthors = Paturle-Lafanechère L, Eddé B, Denoulet P, Van Dorsselaer A, Mazarguil H, Le Caer JP, Wehland J, Job D | title = Characterization of a major brain tubulin variant which cannot be tyrosinated | journal = Biochemistry | volume = 30 | issue = 43 | pages = 10523–8 | date = October 1991 | pmid = 1931974 | doi = 10.1021/bi00107a022 }}</ref> Unlike detyrosination, this reaction is thought to be irreversible and has only been documented in neurons.
* [[Acetylation]]: the addition of an [[acetyl]] group to lysine 40 of alpha-tubulin. This modification occurs on a lysine that is accessible only from the inside of the microtubule, and it remains unclear how enzymes access the lysine residue. The nature of the tubulin acetyltransferase remains controversial, but it has been found that in mammals the major acetyltransferase is [[Alpha-tubulin N-acetyltransferase|ATAT1]].<ref>{{cite journal | vauthors = Kalebic N, Sorrentino S, Perlas E, Bolasco G, Martinez C, Heppenstall PA | title = αTAT1 is the major α-tubulin acetyltransferase in mice | journal = Nature Communications | volume = 4 |
* [[Polyglutamylation]]: the addition of a glutamate polymer (typically 4-6 residues long<ref name="pmid8104053">{{cite journal | vauthors = Audebert S, Desbruyères E, Gruszczynski C, Koulakoff A, Gros F, Denoulet P, Eddé B | title = Reversible polyglutamylation of alpha- and beta-tubulin and microtubule dynamics in mouse brain neurons | journal = Molecular Biology of the Cell | volume = 4 | issue = 6 | pages = 615–26 | date = June 1993 | pmid = 8104053 | pmc = 300968 | doi = 10.1091/mbc.4.6.615 }}</ref>) to the gamma-carboxyl group of any one of five glutamates found near the end of alpha-tubulin. Enzymes related to TTL add the initial branching glutamate (TTL4,5 and 7), while other enzymes that belong to the same family lengthen the polyglutamate chain (TTL6,11 and 13).<ref name="pmid22422711" />
* [[Polyglycylation]]: the addition of a glycine polymer (2-10 residues long) to the gamma-carboxyl group of any one of five glutamates found near the end of beta-tubulin. TTL3 and 8 add the initial branching glycine, while TTL10 lengthens the polyglycine chain.<ref name="pmid22422711" />
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===Tubulin-binding drugs and chemical effects===
A wide variety of [[drug]]s are able to bind to tubulin and modify its assembly properties. These drugs can have an effect at intracellular concentrations much lower than 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]]. However, there are data to suggest that interference of microtubule dynamics is insufficient to block the cells undergoing mitosis.<ref>{{cite journal | vauthors = Ganguly A, Yang H, Cabral F | title = Paclitaxel-dependent cell lines reveal a novel drug activity | journal = Molecular Cancer Therapeutics | volume = 9 | issue = 11 | pages = 2914–23 | date = November 2010 | pmid = 20978163 | pmc = 2978777 | doi = 10.1158/1535-7163.MCT-10-0552 }}</ref> These studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. Suppression of microtubule dynamics by tubulin mutations or by drug treatment have been shown to inhibit cell migration.<ref name=pmid20696757>{{cite journal | vauthors = Yang H, Ganguly A, Cabral F | title = Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs | journal = The Journal of Biological Chemistry | volume = 285 | issue = 42 | pages = 32242–50 | date = October 2010 | pmid = 20696757 | pmc = 2952225 | doi = 10.1074/jbc.M110.160820 | doi-access = free }}</ref> Both microtubule stabilizers and destabilizers can suppress microtubule dynamics.
The drugs that can alter microtubule dynamics include:
* The cancer-fighting [[taxane]] class of drugs ([[paclitaxel]] (taxol) and [[docetaxel]]) block dynamic instability by stabilizing GDP-bound tubulin in the microtubule. Thus, even when hydrolysis of GTP reaches the tip of the microtubule, there is no depolymerization and the microtubule does not shrink back.
▲* The cancer-fighting [[taxane]] class of drugs ([[paclitaxel]] (taxol) and [[docetaxel]]) block dynamic instability by stabilizing GDP-bound tubulin in the microtubule. Thus, even when hydrolysis of GTP reaches the tip of the microtubule, there is no depolymerization and the microtubule does not shrink back.
Taxanes (alone or in combination with platinum derivatives (carboplatine) or gemcitabine) are used against breast and gynecological malignancies, squamous-cell carcinomas (head-and-neck cancers, some lung cancers), etc.
* The [[epothilone]]s, e.g. [[Ixabepilone]], work in a similar way to the taxanes.
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* [[Eribulin]] binds to the (+) growing end of the microtubules. Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.
Expression of β3-tubulin has been reported to alter cellular responses to drug-induced suppression of microtubule dynamics. In general the dynamics are normally suppressed by low, subtoxic concentrations of microtubule drugs that also inhibit cell migration. However, incorporating β3-tubulin into microtubules increases the concentration of drug that is needed to suppress dynamics and inhibit cell migration. Thus, tumors that express β3-tubulin are not only resistant to the cytotoxic effects of microtubule targeted drugs, but also to their ability to suppress tumor metastasis.<ref>{{Cite journal |last1=Altonsy |first1=Mohammed |last2=Ganguly |first2=Anutosh |last3=Amrein |first3=Matthias |last4=Surmanowicz |first4=Philip |last5=Li |first5=Shu |last6=Lauzon |first6=Gilles |date=Mar 2020 |title=Beta3-Tubulin Is Critical for Microtubule Dynamics, Cell Cycle Regulation, and Spontaneous Release of Microvesicles in Human Malignant Melanoma Cells (A375) |journal=International Journal of Molecular Sciences |volume=21 |issue=5 |page=1656 |doi=10.3390/ijms21051656 |pmid=32121295 |pmc=7084453 |doi-access=free }}</ref> Moreover, expression of β3-tubulin also counteracts the ability of these drugs to inhibit angiogenesis which is normally another important facet of their action.<ref>{{
Microtubule polymers are extremely sensitive to various environmental effects. Very low levels of free calcium can destabilize microtubules and this prevented early researchers from studying the polymer in vitro.<ref name="weisenberg" /> Cold temperatures also cause rapid depolymerization of microtubules. In contrast, [[heavy water]] promotes microtubule polymer stability.<ref>{{cite journal | vauthors = Burgess J, Northcote DH | title = Action of colchicine and heavy water on the polymerization of microtubules in wheat root meristem | journal = Journal of Cell Science | volume = 5 | issue = 2 | pages = 433–51 | date = September 1969 | doi = 10.1242/jcs.5.2.433 | pmid = 5362335 }}</ref>
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{{Main|Microtubule-associated protein}}
MAPs have been shown to play a crucial role in the regulation of microtubule dynamics ''in-vivo''. The rates of microtubule polymerization, depolymerization, and catastrophe vary depending on which [[microtubule-associated protein]]s (MAPs) are present. The originally identified MAPs from brain tissue can be classified into two groups based on their molecular weight. This first class comprises MAPs with a molecular weight below 55-62 kDa, and are called [[tau proteins|τ (tau) proteins]]. ''In-vitro'', tau proteins have been shown to directly bind microtubules, promote nucleation and prevent disassembly, and to induce the formation of parallel arrays.<ref>{{cite journal | vauthors = Mandelkow E, Mandelkow EM | title = Microtubules and microtubule-associated proteins | journal = Current Opinion in Cell Biology | volume = 7 | issue = 1 | pages = 72–81 | date = February 1995 | pmid = 7755992 | doi = 10.1016/0955-0674(95)80047-6 }}</ref> Additionally, tau proteins have also been shown to stabilize microtubules in axons and have been implicated in Alzheimer's disease.<ref>{{cite journal | vauthors = Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM | title = Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding | journal = Neuron | volume = 10 | issue = 6 | pages = 1089–99 | date = June 1993 | pmid = 8318230 | doi = 10.1016/0896-6273(93)90057-X | s2cid = 23180847 }}</ref> The second class is composed of MAPs with a molecular weight of 200-1000 kDa, of which there are four known types: MAP-1, [[MAP2|MAP-2]], MAP-3 and [[MAP4|MAP-4]]. MAP-1 proteins consists of a set of three different proteins: [[MAP1A|A]], [[MAP1A|B]] and C. The C protein plays an important role in the retrograde transport of vesicles and is also known as [[Dynein#Cytoplasmic dynein|cytoplasmic dynein]]. MAP-2 proteins are located in the dendrites and in the body of neurons, where they bind with other cytoskeletal filaments. The MAP-4 proteins are found in the majority of cells and stabilize microtubules. In addition to MAPs that have a stabilizing effect on microtubule structure, other MAPs can have a destabilizing effect either by cleaving or by inducing depolymerization of microtubules. Three proteins called [[katanin]], [[spastin]], and fidgetin have been observed to regulate the number and length of microtubules via their destabilizing activities. Furthermore,
MAPs are determinants of different cytoskeletal forms of [[axon]]s and [[dendrite]]s, with microtubules being farther apart in the [[dendrite]]s <ref>{{cite journal |author=Hirokawa, N |title= The neuronal cytoskeleton: roles in neuronal morphogenesis and organelle transport|journal=Molecular Neurobiology: Mechanisms Common to Brain, Skin and Immune System. Series: Progress in Clinical and Biological Research. Willey-Liss, Inc.|volume =390 | pages = 117–143|year = 1994|pmid= 7536943}}</ref>
===Plus-end tracking proteins (+TIPs)===
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{{Main|Microtubule plus-end tracking protein}}
Plus end tracking proteins are MAP proteins which bind to the tips of growing microtubules and play an important role in regulating microtubule dynamics. For example, +TIPs have been observed to participate in the interactions of microtubules with chromosomes during mitosis. The first MAP to be identified as a +TIP was [[CLIP1
===Motor proteins===
[[File:
[[File:Kinesin cartoon.png|thumb|A kinesin molecule bound to a microtubule.]]
Microtubules can act as substrates for motor proteins that are involved in important cellular functions such as vesicle trafficking and cell division. Unlike other microtubule-associated proteins, motor proteins utilize the energy from ATP hydrolysis to generate mechanical work that moves the protein along the substrate. The major motor proteins that interact with microtubules are [[kinesin]], which usually moves toward the (+) end of the microtubule, and [[dynein]], which moves toward the (−) end.
* [[Dynein]] is composed of two identical heavy chains, which make up two large globular head domains, and a variable number of intermediate and light chains. Dynein-mediated transport takes place from the (+) end towards the (-) end of the microtubule. [[Adenosine triphosphate|ATP]] hydrolysis occurs in the globular head domains, which share similarities with the AAA+ (ATPase associated with various cellular activities) protein family. ATP hydrolysis in these domains is coupled to movement along the microtubule via the microtubule-binding domains. Dynein transports vesicles and organelles throughout the cytoplasm. In order to do this, dynein molecules bind organelle membranes via a protein complex that contains a number of elements including [[dynactin]].
* [[Kinesin]] has a similar structure to dynein. Kinesin is involved in the transport of a variety of intracellular cargoes, including vesicles, organelles, protein complexes, and mRNAs toward the microtubule's (+) end.<ref>{{cite journal | vauthors = Hirokawa N, Noda Y, Tanaka Y, Niwa S | title = Kinesin superfamily motor proteins and intracellular transport | journal = Nature Reviews. Molecular Cell Biology | volume = 10 | issue = 10 | pages = 682–96 | date = October 2009 | pmid = 19773780 | doi = 10.1038/nrm2774 | s2cid = 18129292 }}</ref>
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=== Centrosomes ===
[[File:Centriole3D.png|thumb|298x298px|A 3D diagram of a centriole. Each circle represents one microtubule. In total there are 27 microtubules organized into 9 bundles of 3.]]
The [[centrosome]] is the main MTOC ([[microtubule organizing center]]) of the cell during mitosis. Each centrosome is made up of two cylinders called [[
The centrosome is critical to mitosis as most microtubules involved in the process originate from the centrosome. The minus ends of each microtubule begin at the centrosome, while the plus ends radiate out in all directions. Thus the centrosome is also important in maintaining the polarity of microtubules during mitosis.<ref name="pmid9057082">{{cite journal | vauthors = Pereira G, Schiebel E | title = Centrosome-microtubule nucleation | journal = Journal of Cell Science | volume = 110 | issue = Pt 3 | pages = 295–300 | date = February 1997 | doi = 10.1242/jcs.110.3.295 | pmid = 9057082 }}</ref>
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Microtubule plus ends are often localized to particular structures. In polarized [[interphase]] cells, microtubules are disproportionately oriented from the MTOC toward the site of polarity, such as the leading edge of migrating [[fibroblast]]s. This configuration is thought to help deliver microtubule-bound vesicles from the [[Golgi apparatus|Golgi]] to the site of polarity.
Dynamic instability of microtubules is also required for the migration of most mammalian cells that crawl.<ref name="MikhailovGundersen1998">{{cite journal |vauthors = Mikhailov A, Gundersen GG |title = Relationship between microtubule dynamics and lamellipodium formation revealed by direct imaging of microtubules in cells treated with nocodazole or taxol |journal = Cell Motility and the Cytoskeleton |volume = 41 | issue = 4 |pages = 325–40| year = 1998 |pmid = 9858157 |doi = 10.1002/(SICI)1097-0169(1998)41:4<325::AID-CM5>3.0.CO;2-D }}</ref> Dynamic microtubules regulate the levels of key [[G-proteins]] such as [[RhoA]]<ref name="Ren1999">{{cite journal |vauthors = Ren XD, Kiosses WB, Schwartz MA |title = Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton |journal = The EMBO Journal |volume = 18 |issue = 3 |pages = 578–85 |date = February 1999 |pmid = 9927417 |pmc = 1171150 |doi = 10.1093/emboj/18.3.578 }}</ref> and [[Rac1]],<ref name="Waterman-StorerWorthylake1999">{{cite journal |vauthors = Waterman-Storer CM, Worthylake RA, Liu BP, Burridge K, Salmon ED |title = Microtubule growth activates Rac1 to promote lamellipodial protrusion in fibroblasts |journal = Nature Cell Biology |volume = 1 |issue = 1 |pages = 45–50 |date = May 1999 |pmid = 10559863 |doi = 10.1038/9018 |s2cid = 26321103 }}</ref> which regulate cell contractility and cell spreading. Dynamic microtubules are also required to trigger [[focal adhesion]] disassembly, which is necessary for migration.<ref>{{cite journal |vauthors = Ezratty EJ, Partridge MA, Gundersen GG |title = Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase |journal = Nature Cell Biology |volume = 7 |issue = 6 |pages = 581–90 |date = June 2005 |pmid = 15895076 |doi = 10.1038/ncb1262 |s2cid = 37153935 }}</ref> It has been found that microtubules act as
===Cilia and flagella===
Microtubules have a major structural role in eukaryotic [[Cilium|cilia]] and [[Flagellum|flagella]]. Cilia and flagella always extend directly from a MTOC, in this case termed the basal body. The action of the dynein motor proteins on the various microtubule strands that run along a cilium or flagellum allows the organelle to bend and generate force for swimming, moving extracellular material, and other roles. [[Prokaryote]]s possess tubulin-like proteins including [[FtsZ]]. However, prokaryotic flagella are entirely different in structure from eukaryotic flagella and do not contain microtubule-based structures.
===Development===
The cytoskeleton formed by microtubules is essential to the [[morphogenesis|morphogenetic process]] of an organism's [[Developmental biology|development]]. For example, a network of polarized microtubules is required within the [[oocyte]] of ''[[Drosophila melanogaster]]'' during its [[Drosophila embryogenesis|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.<ref name=Van1999>{{cite journal | vauthors = van Eeden F, St Johnston D | title = The polarisation of the anterior-posterior and dorsal-ventral axes during Drosophila oogenesis | journal = Current Opinion in Genetics & Development | volume = 9 | issue = 4 | pages = 396–404 | date = August 1999 | pmid = 10449356 | doi = 10.1016/S0959-437X(99)80060-4 }}</ref> This involvement in the body's architecture is also seen in [[mammal]]s.<ref name=Beddington1999>{{cite journal | vauthors = Beddington RS, Robertson EJ | title = Axis development and early asymmetry in mammals | journal = Cell | volume = 96 | issue = 2 | pages = 195–209 | date = January 1999 | pmid = 9988215 | doi = 10.1016/S0092-8674(00)80560-7 | s2cid = 16264083 | doi-access = free }}</ref>
Another area where microtubules are essential is the [[development of the nervous system]] in higher [[vertebrate]]s, where tubulin's dynamics and those of the associated proteins (such as the microtubule-associated proteins)
===Gene regulation===
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* [https://web.archive.org/web/20141022223450/http://www.mechanobio.info/topics/cellular-organization/go-0005874 MBInfo - Microtubules]
* [http://www.pdbe.org/emsearch/microtubule* 3D microtubule structures in the EM Data Bank(EMDB)]
* [https://puresoluble.com/protocols/ Protocols for generating microtubules]
{{Cytoskeletal Proteins}}
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