Tubulin Post‐Translational Modifications

Abstract

This review describes the enzymes responsible for the post-translational modifications of tubulin, including detyrosinationltyrosination, acetylationldeacetylation, phosphorylation, polyglutamylation, polyglycylation and the generation of non-tyrosinatable a-tubulin. Tubulin tyrosine-ligase, which reattaches tyrosine to detyrosinated tubulin, has been extensively characterized and its gene sequenced. Enzymes such as tubulin-specific carboxypeptidase and a-tubulin acetyltransferase, required, respectively, for detyrosination and acetylation of tubulin, have yet to be purified to homogeneity and examined in defined systems. This has produced some conflicting results, especially for the carboxypeptidase. The phosphorylation of tubulin by several different types of kinases has been studied in detail but drawing conclusions is difficult because many of these enzymes modify proteins other than their actual substrates, an especially pertinent consideration for in vitro experiments. Tubulin phosphorylation in cultured neuronal cells has proven to be the best model for evaluation of kinase effects on tubulinlmicrotubule function. There is little information on the enzymes required for polyglutamylation, polyglycylation, and production of non-tyrosinatable tubulin, but the available data permit interesting speculation of a mechanistic nature. Clearly, to achieve a full appreciation of tubulin post-translational changes the responsible enzymes must be characterized. Knowing when the enzymes are active in cells, if soluble or polymerized tubulin is the preferred substrate and the amino acid residues modified by each enzyme are all important. Moreover, acquisition of purified enzymes will lead to cloning and sequencing of their genes. With this information, one can manipulate cell genomes in order to either modify key enzymes or change their relative amounts, and perhaps reveal the physiological significance of tubulin post-translational modifications.Keywords: tubulin; microtubule ; post-translational modification ; tyrosination ; detyrosination ; non-tyrosinatable ; acetylation; phosphorylation; polyglutamylation ; polyglycylation.Of the three major isotypes of tubulin in eukaryotic cells, atubulin and P-tubulin form heterodimeric complexes which associate head-to-tail into protofilaments and then laterally to make up the wall of the cylindrical microtubule [I-31. The third isotype, y-tubulin, appears in the cytosol and in microtubule-organizing centers as ring-shaped structures where it nucleates microtubules [4-61. Both a-tubulin and P-tubulin, and perhaps y-tubulin [7], exist within most eukaryotic cells as families of closely related isoforms. Isotubulin composition varies spatially and temporally, determined by differential transcription of a-tubulin and P-tubulin genes within small families [2,8,91 and by post-translational modifications of tubulin [I, 8, lo].

Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis

“…Tubulin is subjected to several types of evolutionarily conserved posttranslational modification that includes tyrosination/detyrosination, acetylation, phosophorylation, palmitoylation, polyglutamylation and polyglycylation. [1][2][3][4] The discovery of tyrosination cycle stems from the serial observations that the addition of radiolabeled tyrosine to a rat brain cytosolic extract leads to tyrosination of the COOH terminus of a single endogenous protein, ␣-tubulin, by a translation-independent mechanism. [5][6][7] Posttranslational incorporation of tyrosine into the tubulin has also been shown to occur in vivo.…”

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

“…The carboxyl-terminal regions of both a and h-tubulin undergo numerous posttranslational modifications capable to modulate the function of the microtubule, such as glutamylation, glycosylation, tyrosination, acetylation, and acylation (9,10). Tubulin can also be phosphorylated by several kinases (11), and such changes affect the overall dynamic properties of cellular microtubules during interphase as well as mitosis (11 -14).…”

The Golgi Complex Is a Microtubule-organizing Organelle

“…Such data on the scattering and the reclustering of the Golgi complex have led to the view that Golgi membranes undergo an intimate relationship with MTs and especially with a population of nocodazole-resistant, stable MTs. Stable MTs are characterized by the occurrence of posttranslationally modified tubulin-especially detyrosinated and acetylated tubulin (for review, see MacRae, 1997), which is thought to accumulate in stable MTs because of their longer half-lives, but does not influence MT stability in vivo (Schulze et al, 1987;Khawaja et al, 1988;Webster et al, 1990). Interestingly, not only MT stability influences Golgi localization, but Golgi membranes may reciprocally influence MT stabilization.…”