Principal Investigator Frank Solomon
The microtubule subunit is a heterodimer – unique among cytoskeletal structures. The Éø- and É¿-tubulin polypeptides are quite similar to one another. However, small amounts of undimerized É¿-tubulin are toxic, but cells overexpressing high levels of Éø-tubulin are viable. Undimerized É¿-tubulin arises when the balance between É¿- and Éø-tubulin expression is disrupted; when the heterodimer dissociates; and when there are defects in the folding of Éø-tubulin so that it can not form heterodimer. For example, cells deleted for the minor Éø-tubulin gene TUB3 have ~15 per cent excess É¿-tubulin, and as a result are supersensitive to microtubule depolymerizing drugs and display increased rates of chromosome mis-segregation. Induced expression of high levels of É¿-tubulin causes rapid microtubule disassembly and subsequent cell death. Such severe qualitative defects arising from modest quantitative imbalances are a property of other morphogenetic pathways, such as phage assembly. In the case of microtubule assembly, the data suggest that free É¿-tubulin acts as a dominant interfering protein, competing with the heterodimer for binding to cell components crucial for normal assembly and cell viability.