26.5 : Destabilization of Microtubules

The destabilization of microtubules can occur during different stages of the microtubule lifecycle, such as nucleation or elongation. It can take place at either end of the microtubule or in the microtubule lattices as a whole. The lifespan of individual microtubules within a cell varies according to the cell type and stage of the cell cycle. During interphase, the lifespan of the microtubule is about 30 minutes, while during cell division, it is about 15 minutes. In axonal microtubules of neurons or axonemes of cilia and flagella, the microtubules have a longer lifespan.

Factors that Influence Microtubule Destabilization

Temperature is one of the factors that affect microtubule destabilization. In vitro studies have demonstrated that microtubules disassemble faster at 4°C while rapidly reassembling at 37°C. The next factor is the critical concentration (Cc) of microtubules, which is the concentration of free αβ-tubulin heterodimers at which the net polymerization of the microtubule is zero. The Cc influences the assembly or disassembly of microtubules. The microtubule destabilization occurs at heterodimer concentration lower than that of the Cc. In the cell, the microtubules may undergo abrupt transitions from catastrophe to rescue and vice versa, depending on the Cc.

Some microtubule-associated proteins act as microtubule-destabilizing agents (MDAs). These proteins primarily reduce the concentration of free αβ-tubulin heterodimers, inhibiting their longitudinal interactions with the microtubule. These MDAs facilitate their detachment from the microtubule upon attaching to the tubulin dimers in the protofilaments. Stathmin and kinesin-13 are the two most widely studied destabilizer MAPs responsible for increasing the frequency and duration of microtubule catastrophe.

Microtubule Associated Proteins that Influence Microtubule Destabilization

Stathmin-1 or oncoprotein 18 (Op18) was first discovered as an oncoprotein, highly expressed in breast and ovarian cancers and leukemia. These proteins are regulated by phosphorylation, which inactivates them and prevents their binding to the tubulin subunits. Stathmin is known to play a role in cell death. Stathmin can bind to both free tubulin subunits and those present in the microtubule protofilaments. Binding with free tubulin dimers changes their conformation, preventing their further binding to the microtubule filaments. In protofilaments, these destabilizing agents cause bending of the filaments, facilitating the removal of tubulin dimers.

Kinesin-13, a non-motile member of the kinesin superfamily, has its conserved motor domain at the center instead of the N- or C-terminal like other kinesins. This destabilizer reduces affinity between the tubulin subunits within the microtubule. Katanin, another microtubule destabilizer, has two subunits that sever the longitudinal bonds between the protofilaments of a microtubule. During cell division, katanin detaches microtubules from the centrosomes causing rapid destabilization of the spindle fibers. Their role in destabilizing microtubules has also been observed during interphase in proliferating cells.