Microtubule cryptography: the effects of tubulin diversity on polymer structure, dynamics and readout by cellular effectors

Microtubules are essential non-covalent polymers composed of -tubulin subunits. Deceptively uniform ultrastructurally, microtubules are mosaic and contain multiple tubulin isoforms functionalized with abundant posttranslational modifications. Tubulin isoforms and posttranslational modifications vary widely between cell types and their patterns are stereotyped, suggesting roles in spatial and temporal control. An increasing body of evidence supports the hypothesis that the combinatorial information expressed through tubulin genetic and chemical diversity controls microtubule dynamics, mechanics and interactions with microtubule effectors and thus constitutes a “tubulin code”. Although discovered over thirty years ago, a mechanistic understanding of the tubulin code has remained elusive. I will present two studies from my lab that illustrate how the tubulin code can regulate microtubule properties in cis, by directly affecting microtubule structure and dynamic instability, and in trans, by precisely controlling the activity of a microtubule effector, a microtubule severing enzyme. (1) I will discuss our recent data that reveals how varying tubulin isoform composition proportionally tunes microtubule dynamic parameters and (2) I will discuss our data that demonstrates that glutamylation, a posttranslational modification that involves the addition of variable numbers of glutamates to the intrinsically disordered tubulin C-terminal tails acts as a rheostat and tunes microtubule severing as a function of glutamate number added per tubulin. Unexpectedly, glutamylation is a non-linear biphasic tuner and becomes inhibitory beyond a threshold. Furthermore, the inhibitory effect of localized glutamylation propagates across neighboring microtubules, modulating severing in trans. This work provided the first quantitative evidence for a graded, spatially controlled response to a tubulin posttranslational modification and constitutes an essential step towards understanding how the cell interprets the tubulin code.