Post-translational modifications (PTMs) are highly dynamic and often reversible processes in which the functional properties of proteins are changed by adding chemical groups or other proteins to the amino acid residues. Tubulins and thus microtubules (MTs) are important target substrates for a large number of PTMs because they play a key role in cytoskeletal development and therefore play an important role in neuronal development, growth, cell motility and intracellular transport. The post-translational modifications include tyrosination or detyrosination, α2-tubulin formation, acetylation, phosphorylation, polyamination, ubiquitination, polyglutamylation and glycination (see figure). Most of these PTMs usually take place on tubulin subunits already built into microtubules.
The PTMs convey various properties:
Tubulin acetylation usually occurs with stable microtubules. Acetylation does not directly stabilize MTs but modifies the behavior of the proteins in the MT lumen.
Detyrosination of the C-terminal tyrosine of α-tubulin prevents the depolymerization of the microtubules and thereby increases their half-life.
Polyglutamylation, i.e. the formation of polyglutamate chains on the γ-carboxyl groups of glutamate residues is particularly pronounced during the differentiation of neuronal tissue. Polyglutamylation also regulates the stroke behavior of motile cilia by influencing the flagellar dynein motor. By activating microtubule-degrading enzymes such as spastine, polyglutamylation also stimulates MT turnover.
Tubulin polyglycination is the addition of glycine chains to the C-terminal domains of α- and β-tubulin. Polyglycination stabilizes the axonem – the central microtubule structure in cilia and flagella with the well-known 9×2 + 2 structure.
PTMs on microtubules generate a “tubulin code” that influences the biological functions of the MT cytoskeleton. The PTMs perform their function here by modulating higher MT structures and / or interactions with certain MT-associated proteins (MAPs, motor proteins, etc.). Microtubules are involved in various biological processes in practically every cell in the body. If this filigree regulated system is disturbed, this is an important factor in the development and clinical manifestation of Alzheimer’s, Parkinson’s and cancer.