title: Graded Control of Microtubule Severing by Tubulin Glutamylation.
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. 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 response to a tubulin posttranslational modification and a biochemical link between tubulin glutamylation and complex architectures of microtubule arrays such as those in neurons where spastin deficiency causes disease.
authors.affiliation: Cell Biology and Biophysics Unit, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: Max L
authors.initials: ML
authors.lastname: Valenstein
authors.affiliation: Cell Biology and Biophysics Unit, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA; National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA. Electronic address: antonina@mail.nih.gov.
authors.forename: Antonina
authors.initials: A
authors.lastname: Roll-Mecak
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D001696:Biomechanical Phenomena; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D015202:Protein Engineering; D011499:Protein Processing, Post-Translational; D015419:Spastic Paraplegia, Hereditary / Q000378:metabolism* / Q000473:pathology; D000074181:Spastin; D014404:Tubulin / Q000378:metabolism*
chemical_list: D014404:Tubulin; D018698:Glutamic Acid; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human