European Journal Of Neuroscience Animation Essay

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Microtubules (MTs) play a large role in cell motility, like the beating of cilia and flagella as well as transport of vesicles in the cytoplasm. Cell motility is achieved by polymerisation and depolymerisation of the microtubules. Apart from this, it has also a vital part in meiosis and mitosis in the attachment of spindle fibres to chromosomes and their separation from one another (Figure 1).

Microtubules originate from the microtubule-organising center (MTOC); this latter is responsible for the assembly of microtubules and orientation of organelles and microtubule, and finally the direction of vesicle trafficking. Microtubules are hollow cylinders made from tubulin subunits, measuring 25nm in diameter. The heterodimer tubulin is made of two subunits, a- and ß-tubulin dimers. These two tubulin dimers polymerise to form protofilaments which are part of the longitudinal interaction between them. However there is also a lateral interaction between the subunits and it is a mix of these two interactions which hold microtubules in a tubular form, made of 13 protofilaments. Microtubules also show polarity.

There is a plus (+) end and a minus (-) end to microtubules; when polymerising, tubulin subunits add to the (+) end and there is a capping process happening at the (-) end. Both subunits bind guanosine triphosphate (GTP), and the GTP bound a-tubulin is stable and irreversible but the GTP bound ß-tubulin isn't and it will be hydrolysed to GDP (guanosine diphosphate). Further more only the GDP bound tubulin can depolymerise and therefore it is the GTP bound end which acts as a cap at that end of the microtubule.

Microtubule-based motor proteins dynein and kinesin are associated with vesicle and organelle movement along MT. Dynein is said to be minus-end directed as it transports vesicles towards the minus-end of the microtubule which is also orientated towards the center of the cell whereas kinesin, is a plus-end directed motor protein orientated towards the cell surface. Dynein can be divided into two groups, axonemal dynein which is associated with the beating of cilia and flagella, and cytosolic dynein which moves chromosomes and vesicle. Axonemal dynein has an "axoneme" structure made of nine microtubule pairs in circle and a single doublet in centre giving it the 9+2 array, the outer doublets of the axoneme slide past each other. Energy for movement is provided through hydrolysis of ATP by dynein. This latter, in contrast to kinesin, cannot mediate transport by itself (Lodish et al., 2003). Rather, it uses microtubule-binding proteins (MBPs) to connect chromosomes and vesicles to MT. One example of such MBP, a large heterocomplex, dynactin binds dynein to make the dynein-dynactin complex which can now mediate transport of chromosomes and vesicles. Kinesin is composed of two heavy chains and two light chains both attached to a coiled-coil dimer which forms the a-helical neck. Like dynein, kinesin can be grouped into two subcategories, i.e. cytosolic kinesin which has a role in vesicle and organelle transport, and mitotic kinesin, which helps spindle assembly and chromosome movement.

"Catastrophe" happens when the hydrolysis of GTP to GDP at the (+) end happens faster than the addition of GTP tubulin at the (-) end. This is rescued by addition of new GTP binding tubulin. It can be said that microtubules show dynamic instability. Microtubules keep growing as long as the free tubulin concentration is higher than the critical level; however, sometimes microtubules suddenly stop growing and start to shrink rapidly. This shrinkage is stopped by the "rescue" process (Figure 2). This procedure doesn't happen to all microtubules at the same time and therefore other microtubules will keep on growing normally. In other words, growing and shrinking of microtubule is independent of its neighbours.

Microtubule- associated proteins (MAPs) bind directly to tubulin subunits on the microtubule and are in charge of their assembly or disassembly by cycles of polymerisation and depolymerisation. There are two types of MAPs, type I consist of MAP1 proteins whilst type II comprise MAP2, MAP4 and tau proteins. Tau, which is responsible for MT assembly, is famously related to Alzheimer's disease. Hyperphosphorylation of tau protein causes self-aggregated tangles in nerve cells. However, it is necessary for tau proteins to be phosphorylated in some degrees for MT assembly and stabilise its structure. (de Ancos et al., 2003). Nevertheless, neither hyperphosphorylation nor unphosphorylation is beneficial to tau as the first leads to the incurable form of dementia. In addition, type II MAPs bind tubulin at their C-terminal ends and project outward the microtubule with their N-terminal ends to network with other microtubule and cytoplasmic organelles (Figure 3). It can be concluded from that, that one of their function is to mediate interactions and control spacing of microtubules inside the cell. The most important MAPs are found in nerve cells, MAP2 is found in dendritic cells while tau proteins are found in axons and finally MAP4 is found in non-neuronal cells. This latter has been found to increase the chances of a "rescue" without affecting the rate of "catastrophe", hence stabilising MTs. Also, MAP4 was found to"...lower the critical concentration of tubulin required for assembly..." (Aizawa et al., 1987, 1991).

Phosphorylation of some MAPs causes bonds to break between the microtubule and MAPs, thus reducing their effect. However this isn't the case for MAP4 whose bond with microtubules remains unchanged when phosphorylated, in contrast, its ability to increase the chances of a rescue are diminished. Phosphorylation of MAP4 is carried out by CDC2 kinase (Ookata et al., 1997). MAP4-microtubule binding can however be inhibited by mapmodulin, a soluble protein, which binds to MAP4 and I believe, acts as a competitive inhibitor by preventing microtubules to bind to MAP4.

Other microtubule stabilisers include XMAP230 and XMAP310. As opposed to MAP4, XMAP230 doesn't promote a "rescue" but reduces the rate of "catastrophes". On the other hand XMAP310 does what MAP4 does but the effects of its inhibition are not yet clear (Cassimeris, 1999).

Other proteins can destabilise MT, these include the oncoprotein 18 (Op18)/stathmin, mitotic centromere-associated kinesins (MCAK), katanin, as well as XKCM1. The latter is part of the kinesin-superfamily; its role is to boost "catastrophes" by means of an ATP-dependent mechanism. Another group of proteins belonging to the kinesin-superfamily is MCAK linked to MT polymer loss in mitosis and interphase (Maney et al., 1998). Katanin is a severing protein which cuts MTs to destabilise them, by doing so, free-ends become exposed. At the same time, this is beneficial for the mobility of microtubules in the cytoplasm during development. Op18, also known as stathmin, has for function to reduce the concentration of tubulin below the critical concentration, it does so by binding mainly to soluble a-tubulin; this in turn amplifies "catastrophe" as a low concentration of tubulin dimers means a higher frequency of "catastrophes". What's more, Op18 only binds to tubulin dimers rather than assembled MTs. Nevertheless activity of Op18 can be halted by phosphorylation in mitosis.

Several proteins which interact with microtubule have been recently found, from microtubule-based motor proteins to microtubule-associated proteins, all assist MT in its functions in cell motility. From movements to assembly and disassembly of MT, these proteins are modified and helped along either by phosphorylation or other protein complexes which bind to it. The regulation of these proteins changes MT dynamics to ensure its fast turnover during cell division. To conclude it is a combination of different proteins and a right balance between stabilising and destabilising-proteins which is necessary for MT to carry out its functions during its time in the cytoskeleton.

References:

  • Brachet. J, 1985. Molecular Cytology, Volume1, The Cell Cycle.
  • H. Lodish, A. Berk, S. L. Zipursky, P. Matsudaira, D. Baltimore, J. E. Darnell. 19.3 Kinesin, Dynein, and Intracellular Transport. Molecular cell biology. New York: W. H. Freeman & Co. 1999
  • Li. H, D. J DeRosier, W. V. Nicholson, E. Nogales, K. H. Downing. 2002. Microtubule structure at 8 A resolution.
  • L. Cassimeris, 1999. Accessory protein regulation of microtubule dynamics throughout the cell cycle. J Cell Biol. (1999) pp. 134-141.
  • Amos. LA. Tubulin and Microtubules. Medical research council.
  • H. L Nguyen, D. Gruber, J. C. Bulinski, 1999. Microtubule-associated protein 4 (MAP4) regulates assembly, protomerpolymer partitioning and synthesis of tubulin in cultured cells. Journal of Cell Science 112, 1813-1824, 1999.
  • K. Ookata, S. Hisanaga, M. Sugita, A. Okuyama, H. Murofushi, H. Kitazawa, S. Chari, J. C. Bulinski,T. Kishimoto, 1997. MAP4 Is the in Vivo Substrate for CDC2 Kinase in HeLa Cells: Identification of an M-Phase Specific and a Cell Cycle-Independent Phosphorylation Site in MAP4. Biochemistry, 36, 15873-15883, 1997.
  • F. Liu, B. Li, E. Tung, I. G. Iqbal, K. Iqbal, C. Gong, 2007. Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation. European Journal of Neuroscience, Vol. 26, pp. 3429-3436, 2007.
  • http://www.cytochemistry.net/Cell-biology/microtubule_intro.htm

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