Tubulin dynamic instability

Hydrolysis of E-site GTP during or shortly after addition of tubulin to the microtubule ends and the gain and loss of a short region of GTP-(or GDP-Pi)-liganded tubulin at the extreme ends of the microtubules that stabilize the microtubule tips are believed responsible for dynamic instability. The tubulin dimer has intrinsic GTPase activity, with a rate that is relatively slow when tubulin is in solution (21). However, hydrolysis is triggered when the 3-subunit of an incoming tubulin dimer with bound GTP docks at the end of an exposed a-subunit... 

The GDP-tubulin subunits in the interior length of a microtubule remain stably polymerized, whereas GDP subunits exposed at an end have a strong tendency to dissociate. Marc Kirschner and Tim Mitchison found that some microtubules in a population lengthen while others simultaneously shorten. This property, called dynamic instability, arises from random fluctuations in the number of GTP- or GDP-tubulin subunits at the plus end of the polymer. The dynamic character of microtubules is crucial for processes such as mitosis, which require the assembly and disassembly of elaborate microtubule-based structures. 

FIGURE 20-11 Dynamic instability model of microtubule growth and shrinkage. GTP-bound a(3-tubulin subunits (red) add preferentially to the (-t) end of a preexisting microtubule. After incorporation of a subunit, the GTP (red dot) bound to the (i-tubulin monomer is hydrolyzed to GDP Only microtubules whose (+) ends are associated with GTP-tubulin (those with a GTP cap) are stable and can serve as primers for the polymerization of additional tubulin. Microtubules with GDP-tubulin (blue) at the (+) end (those with a GDP cap) are rapidly depolymerized and may disappear within 1 minute. At high concentrations of unpolymerized GTP-tubulin, the rate of addition of tubulin is faster than the rate of hydrolysis of the GTP bound in the microtubule or the rate of dissociation of GTP-tubulin from microtubule ends thus the microtubule grows. At low concentrations of unpolymerized GTP-tubulin, the rate of addition of tubulin is decreased consequently, the rate of GTP hydrolysis exceeds the rate of addition of tubulin subunits and a GDP cap forms. Because the GDP cap is unstable, the microtubule end peels apart to release tubulin subunits. [See T Mitchison and M. Kirschner, 1984, Nature 312 237 ... 

Microtubules exhibit two dynamic phenomena that are pronounced at tubulin concentrations near the Q (1) tread-milling, the addition of subunits at one end and their loss at the other end, and (2) dynamic instability, the oscillation between lengthening and shortening (see Figure 20-9). 

Tubulin binding agents interfere with the dynamic instability of microtubules and thereby arrest mitotic cells in the M-phase of the cell division cycle, finally leading to induction of apoptosis. Most, if not all, tubulin inhibitors bind within fl-tubulin to distinct epitopes. They are... 

The fast growing plus-ends of the microtubules are usually oriented toward the cell periphery, while the minus-ends are embedded in the centrosome or microtubule-organizing center (p. 372). Just as with actin, in which bound ATP is hydrolyzed to ADP, the bound GTP in the P-tubulin subunits of microfubules is hydrolyzed to GDP decreasing the stability of the microtubules, a phenomenon described as dynamic instability. Various microtubule-associated proteins (MAPs) have strong effects on this phenomenon. ... 

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