Intracellular transport
Intracellular transport

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Intracellular transport

1.3 Polymerisation and depolymerisation of tubulin

Polymerisation of microtubules is similar in concept to microfilament polymerisation, but different in almost every detail. The basic subunit of the microtubule is the tubulin heterodimer, consisting of an α-tubulin and a β-tubulin monomer, which are firmly associated with each other. These assemble end-to-end to form filaments. The overall assembly consists of a ring of 13 such filaments arranged into a microtubule with a plus and a minus end (Figures 5 and 6). The minus ends of the tubules are stabilised and nucleated within the MTOC by γ-tubulin, which effectively acts as a capping protein. The plus ends of the microtubules are stabilised by other capping molecules or by attachment to organelles.

Figure 5 A molecular model of the tubulin heterodimer. The α-chain (top) and β-chain (bottom) are structurally very similar, and both bind to one molecule of GTP, shown as a space-filling model in purple; α helix is shown in red, β sheet in blue, and regions lacking secondary structure in green.
Figure 6 Microtubule structure and assembly. Heterodimers of α-tubulin and β-tubulin assemble end-to-end to form filamants, with α-tubulin at the plus end. Thirteen filaments assemble in a ring to form a microtubule.

Both α- and β-tubulin units bind to GTP and act as GTPases. In the presence of GTP and Mg2+ ions, polymerisation is favoured and the tubules extend from the plus end of the tubule, forming a GTP cap. GTP is progressively hydrolysed by the tubulin, and tubulin-GDP dissociates more readily from the tubule than tubulin-GTP. These characteristics lead to the behaviour known as dynamic instability. This is the observation that microtubules grow slowly from the plus end and then tend to shrink back suddenly, which can be explained in terms of the reactions above.

Consider the plus end of a microtubule. Provided the concentration of tubulin-GTP is above the critical value, the tubule will continue to grow by addition of new tubulin-GTP monomers, and new monomers will be added before the previous ones have had time to hydrolyse their GTP. Consequently a tubule with a GTP cap will grow slowly. If, however, the concentration of tubulin-GTP falls below the threshold, or the conditions for polymerisation change, new monomers are added too slowly and tubulin-GDP subunits in the microtubule become exposed. As these dissociate more quickly, the tubule will shrink rapidly, until it is rescued by the addition of new tubulin-GTP dimers (Figure 7). Dynamic instability is also seen in actin microfilaments, for the same reasons, but as the rate of growth and retraction of microfilaments is lower than that of microtubules, the effect is less dramatic.

Figure 7 Dynamic instability of tubulin. Microtubules grow slowly by the addition of tubulin-GTP to the plus end of the tubule. The GTP cap so formed is relatively stable (a) but if the tubule loses its cap (b) tubulin- GDP is exposed and the tubule retracts rapidly with dissociation of tubulin-GDP heterodimers (c). (Note that, for simplicity, only one of the 13 filaments in the microtubule is shown.)

Although you may have gained the impression that microtubules are very dynamic, some microtubules are permanent features of the cell. For example, in neurons, bundles of microtubules extend all the way down axons from the cell body to the nerve terminal. Such bundles are stabilised by cross-linking proteins that bind to the sides of microtubules and are called microtubule associated proteins (MAPs). A MAP called tau, which cross-links bundles of microtubules in axons, has received a lot of attention in recent years, because of the possibility that it is involved in the development of Alzheimer's disease. Tau has multiple tubulin-binding domains that allow it to cross-link microtubules at regular intervals. Thus a nerve axon may contain a bundle of hundreds of regularly spaced, cross-linked microtubules. Cross-linking of the tubules is modulated by the phosphorylation of tau, and one theory proposes that phosphorylation of tau is abnormal in people with Alzheimer's disease. In the case of nerve axons, the bundle of microtubules serves two functions: it acts as a structural element of the cell, giving stability to the axon, but it also acts as a trackway for the transport of vesicles.

For this reason, it is thought that the microtubule networks must be subject to some degree of remodelling, in order to facilitate vesicular traffic, but that this is limited by the requirement to maintain axon structure. The ‘tau hypothesis’ of Alzheimer's disease suggests that the balance of these functions is disturbed so that normal axon structure and neuronal function are impaired.

Numerous other proteins associate with microtubules and perform analogous functions to those proteins that associate with microfilaments, including stabilisation, destabilisation and cutting. For example, the protein catastrophin pulls apart the plus end of microtubules and promotes dynamic instability.

  • Can you think of one place in the cell where microtubule-capping proteins would be located during mitosis?

  • The centromeres of the chromosomes have capping proteins that attach to microtubules emanating from the mitotic spindles. These serve to stabilise the microtubules during mitosis and to act as attachment points on the chromosomes.

Before going on to look in more detail at the function of microtubules in facilitating intracellular traffic, we shall complete our review of the cytoskeleton by looking at intermediate filaments.


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