Microtubules are key cytoskeletal elements involved in a large number of functions in eukaryotic cells.
They assemble from a protein dimer of a- and b-tubulin, two highly similar and conserved proteins. Tubulins are subject to a large variety of posttranslational modifications (Fig. 1), which provide a rapid and reversible mechanism to diversify microtubule functions in cells. Our team is studying the mechanisms and functional roles of these modifications by using an interdisciplinary approach.
Our team has identified the enzymes involved in the posttranslational polyglutamylation (1, 2), deglutamylation (3, 4) and polyglycylation (5) of tubulin. Following the discovery of these enzymes, we are now investigating (i) the molecular mechanisms, and (ii) the biological functions of tubulin-modifying enzymes.
Polyglutamylation and polyglycylation take place within the C-terminal tails of the tubulin molecules. These tails are localized at the outer surface of the microtubule (Fig. 1), thus their posttranslational modification is most likely regulating the interactions of microtubules with their multiple binding partners, commonly known as microtubule-associated proteins (MAPs) and molecular motors. So far we have demonstrated that the microtubule-severing protein spastin is regulated by tubulin polyglutamylation (6), and that tubulin glycylation stabilizes ciliary axonemes by a yet unknown molecular mechanism (5, 7). Our functional studies have demonstrated an important role for both, polyglutamylation and polyglycylation for motile and primary cilia in mammals (7, 8), and we have found that polyglutamylation is directly linked to neurodegeneration in mice (4). We have further demonstrated a direct link between altered levels of a tubulin glycylase and colorectal cancer development (8).
In our ongoing projects, we are using biochemistry, biophysics and structural biology in conjunction with cell and mouse biology to identify the molecular mechanisms by which tubulin posttranslational modifications regulative microtubule behaviour and functions, and which are the cellular and developmental roles of these modifications and the corresponding enzymes. Our functional studies are focussed on the nervous system, cilia and flagella (including spermatogenesis), and cell division. Our team is closely collaborating with clinicians to delineate the implications of tubulin posttranlsational modifications in human pathologies.