The regulatory machinery of tubulin detyrosination

Not only our body has a skeleton, but also each of our cells possesses a skeleton the so called cytoskeleton, which among others is built up by long filamentous structures which are named microtubules. In contrast to our bone skeleton, the cytoskeleton is greatly flexible and dynamic. It adapts quickly to the needs of the cell by shrinking, growing or re-arranging the microtubules. This adaptability allows microtubules to participate in a wide range of different cellular processes. Microtubules play a crucial role in the correct segregation of our genetic material (chromosomes) during cell division, give the cell the right mechanical stiffness and serve as transportation tracks within the cell. In addition to this universal functions in all cells of the body, microtubules are also important for more specialised function in certain cell types. For example, neurons use microtubules to supply their nerve ends over long distances, microtubules contribute to the contractions of heart cells and are indispensable for cell motility for some cells like sperm cells. How can simple cell structures such as microtubules fulfil so many different functions? How does the cytoskeleton know when to exert which function? To instruct microtubules they are marked. One type of marks is called detyrosination. It has its name from the fact that the last amino acid (a tyrosine) of the microtubule building block alpha-tubulin is removed. Detyrosinated microtubules are therefore marked and allow only certain proteins to interact with them. This tyrosine- dependent protein interaction translates subsequently into a particular function. It has been shown that defects in detyrosination can contribute to neurological disorders and heart failure. During my post-doctoral stay at the Netherlands Cancer Institute (NKI) I identified a novel enzyme, which can detyrosinate microtubules. This discovery allows me to explore now the regulation of detyrosination. To do so, I make use of haploid genetic screens a method that can test in a single experiment the influence of all genes of our genome on detyrosination. Ultimately, I hope to understand when and how the microtubule-dependent cytoskeleton is detyrosinated and how defects in this regulatory machinery contribute to diseases.

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