Harnessing new tools to probe tubulin tyrosination

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11 April 2022

Microtubules are hollow rods that form an important part of the cell cytoskeleton. They are built from polymers of tubulin, a protein that can be modified by the removal (or later re-addition) of an amino acid called tyrosine. Tyrosine modification can affect how the microtubules interact with kinesins, which walk along the microtubules and carry cargo from one part of the cell to another. Proper kinesin function is particularly important in neurons, since these cells can reach remarkable lengths and so transporting cargo from one end to another is a significant undertaking.

Agustina Zorgniotti is a PhD student in Dr Gastón Bisig’s lab at the Centro de Investigaciones en Química Biológica, Argentina. The Bisig group has been using tyrosine analogues to investigate the physiological importance of tyrosination. L-Dopa is a tyrosine analogue of particular interest because it is thought that it cannot be released from microtubules once incorporated. It is also currently used as a drug to treat patients suffering from Parkinson’s disease.

Tyrosine release is usually catalysed by the tubulin carboxypeptidase (TCP) enzyme. This enzyme has recently been shown to be made up of two components: vasohibins (VASH) and a small vasohibin binding protein (SVBP). Purified VASH/SVBP complexes are able to remove tyrosine from polymerised microtubules, and this encouraged Agustina to harness these complexes as a new tool to probe the irreversibility of L-Dopa incorporation.

With the help of a Travelling Fellowship from Journal of Cell Science, Agustina visited Dr Marie-Jo Moutin’s lab at the Grenoble Institut de Neurosciences, France. Dr Moutin’s lab was one of the groups that identified VASH and SVBP as components of the TCP enzyme, so Agustina was keen to initiate a collaboration with them.

During her stay, Agustina found that the VASH/SVBP complexes were in fact able to cleave L-Dopa from tubulin, but that the efficiency of this process was dramatically reduced compared with the process of tyrosine removal. Agustina also demonstrated that VASH remained bound to L-Dopa microtubules for a shorter period than it did to tyrosinated microtubules. Finally, experiments using neurons gave insight into the importance of proper tyrosination in cells, since treatment with L-Dopa resulted in slower neuronal development.

As well as generating important data for her thesis, Agustina notes that the visit was enriching in other ways. “I met many outstanding researchers and students with whom I had enriching discussions,” she said “Moreover, I received a warm welcome from the people in the lab, and their hospitality and kindness allowed me to feel comfortable from the beginning. We did different activities that allowed me to learn about the culture and discover stunning places in Grenoble and the surroundings. Overall, I consider my stay as a rewarding experience not only for my professional career but also for my personal growth”.

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