Abstract
Microtubule-severing enzymes are critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia where tubulin detyrosination, acetylation and glutamylation are abundant. These modifications exhibit stereotyped patterns suggesting spatial and temporal control of microtubule functions. Using human engineered and differentially modified microtubules we find that glutamylation is the main regulator of the hereditary spastic paraplegia microtubule severing enzyme spastin and that neither detyrosination nor acetylation regulate spastin activity. Glutamylation 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. Our work provides 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. Furthermore, it provides a biochemical link between tubulin glutamylation and complex architectures of microtubule arrays such as those in neurons where spastin deficiency causes disease.
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