Researchers of the Netherlands Cancer Institute, the Hubrecht Institute and Utrecht University, have now solved this puzzle. They managed to do this through an innovative genetic screening method published in Nature last May, that was developed by amongst others Maarten Altelaar and three other authors of the Science-publication. For this they used genome wide random mutations in human cells, containing just one copy of each gene. Then they selected the cells in which the studied process of detyrosination was broken, due to one of the randomly introduced mutations. Subsequently they analysed the cells with very little detyrosinated tubulin and discovered they had a mutated (and therefore dysfunctional) SVBP gene.
This led them to identify the small SVBP protein as being a crucial part of the process. This small protein binds - and thereby stabilizes - proteins called vasohibins, which appear to have tubulin detyrosination activity. Nieuwenhuis: "These findings are surprising, because vasohibins were thought to function outside the cell and only recently it was predicted that these proteins might function as enzymes, without knowing their function."
Further experiments confirmed the interaction with vasohibins and its effect on tubulin detyrosination. For part of this confirmation, the characterization of the N-terminal tail of the protein, a method developed by the Biomolecular Mass Spectrometry and Proteomics group of Utrecht University was applied. This method was published in Nature Methods in 2008.
"For cell biologists this could be an important step", says Nieuwenhuis. "We have found a piece of the puzzle that scientist have been staring at for many years because the process of detyrosination was discovered 40 years ago. This knowledge could be relevant to further understand the processes of mitosis, cell migration and cancer development. It is already found that the invasive front in some tumour tissues, where cells are migrating most actively, contains a high amount of detyrosinated tubulin. It is interesting to speculate that inhibition of detyrosination could be beneficial under certain conditions."
Interestingly, in the same edition of Science a group of French scientists reached similar conclusions using a biochemical approach to identify detyrosinating enzymes.
Vasohibins encode tubulin detyrosinating activity
Joppe Nieuwenhuis, Athanassios Adamopoulos, Onno B. Bleijerveld, Abdelghani Mazouzi, Elmer Stickel, Patrick Celie, Maarten Altelaar, Puck Knipscheer, Anastassis Perrakis, Vincent A. Blomen, Thijn R. Brummelkamp
Science, 16 November 2017
This news item is a slightly adapted version of the press release of NKI.