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A crucial enzyme for neurons unveiled at last!

on the December 4, 2017

Identification of the enzyme responsible for the tubulin detyrosination that was searched since 40 years

Caroussel_17.12.12_Moutin_Enzyme_EN.jpg

The team "Physiopathologies of the Cytoskeleton" has finally identified the enzyme responsible for the tubulin detyrosination that was searched since 40 years. This work opens up new prospects for improved understanding of the role played by this tubulin modification, deregulation of which has been linked to cancers, cardiovascular diseases and neural disorders. These results were published on 16th November 2017 in the journal Science.

Microtubules are dynamic fibres present in cells formed by the combination of alpha-tubulin and bêta tubulin (alpha/bêta dimers). Microtubules are involved in cell division, cellular polarity, morphology and migration. These cellular functions are regulated by signals which are present on the surface of microtubules. These signals, consisting of biochemical modifications to amino acids (known as post-translational modifications, as they take place after protein synthesis), occur at multiple sites in cells and are executed by a broad range of enzymes.

The activity of one of these enzymes was first identified in 1977 by an Argentinian research team. They named this activity “TCP” (Tubulin CarboxyPeptidase). This enzyme was shown to perform the detyrosination reaction: removal of the terminal amino acid, a tyrosine, from the end of alpha-tubulin, but the protein itself remained to be identifie). Another enzyme, the ligase TTL (Tubulin Tyrosine Ligase), performs the reverse reaction – tyrosination – through which the tyrosine is replaced. The detyrosination/tyrosination cycle is vital for the cell and the organism as a whole. Massive (abnormal) detyrosination is observed in a number of severe cancer types and in cardiovascular diseases. A few years ago, the team Physiopathology of the Cytoskeleton showed that mice that do not express the TTL died just after birth because their brain did not develop correctly.

In the recent work to identify TCP, the team monitored its activity, used conventional biochemical techniques, and collaborated with chemists from Stanford University, who developed a small molecule inhibiting its activity. This molecule was then used as bait to “trap” the elusive enzyme lowly expressed in tissue.

Two enzymes were discovered. VASH1 and VASH2 were already known to scientists, but they had not previously been associated with the cytoskeleton. The researchers demonstrated that, when associated with a partner protein called SVBP, VASH1 and VASH2 can cause detyrosination of alpha-tubulin. The team down-regulated the expression of VASH1/2 (or their partner SVBP) in neurons. In both cases, a very strong decline in the level of detyrosination of alpha-tubulin was observed along with altered neuronal morphology (see Figure). Neuronal differentiation was delayed. In collaboration with Team "Neural progenitors and brain pathologies", the researchers also demonstrated that these enzymes are involved in cerebral cortex development.
 

Alterations to neurons as a result of reduced expression of TCP enzymes (VASH/SVBP). From left to right: control neuron, neurons expressing reduced levels of VASH1 and VASH2, neurons expressing reduced SVBP levels. Development is delayed in neurons with reduced enzyme levels, and morphological anomalies are seen. © L. Peris, GIN


Tubulin detyrosination/tyrosination cycle.
Microtubules are fibres which are present in cells, comprised of a stack of ?/? tubulins. ?-tubulin has a tyrosine (Y) at its extremity, which is alternately removed and replaced by two enzymes, thereby modifying the microtubule’s surface. TCP (represented by a saw composed of two elements, VASH/SVBP) is responsible for detyrosination. TTL (represented by a tube of glue) replaces tyrosine on the tubulin. This cycle is essential to the various roles played by microtubules in cells (division, migration, etc.) and is vital for the organism as a whole. © C. Bosc, GIN

Scientists are now hoping that, by modulating TCP activity and improving their knowledge of the detyrosination/tyrosination cycle, they will be able to gain a better understanding of its cerebral and cardiac functions and to develop new treatments for specific diseases (including cancers).

Interestingly, other scientist in Netherlands also identified these proteins as the tubulin detyrosinating enzymes using a very different - genetic - approach. Their work is published in the same edition of Science.


Reference:

Vasohibins/SVBP are tubulin carboxypeptidases (TCP) that regulate neuron differentiation.
Aillaud C, Bosc C, Peris L, Bosson A, Heemeryck P, Van Dijk J, Le Friec J, Boulan B, Vossier F, Sanman LE, Syed S, Amara N, Couté Y, Lafanechère L, Denarier E, Delphin C, Pelletier L, Humbert S, Bogyo M, Andrieux A, Rogowski K, Moutin MJ. Science. 2017 Nov 16. doi: 10.1126/science.aao4165. 



Updated on December 12, 2017

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