Researchers from the Carl R. Woese Institute for Genomic Biology, in collaboration with scientists from the University of Oxford, published an article in Cell reporting the function of LanCL proteins. These proteins are found in eukaryotic cells but their function was previously unknown. The study is the first step towards understanding the importance of these ubiquitous proteins.
Bacteria contain enzymes called LanC capable of producing small proteins called lanthipeptides, characterized by the addition of a thiol group to a modified serine or threonine amino acid. Similar proteins – called LanC-like or LanCL – have been found in different eukaryotic cells for decades, but their function was unknown.
“LanCLs are found in almost all higher organisms, including humans. Although scientists have worked on these proteins for over 20 years, we did not know their function. We had several hypotheses, which we continued to rule out. based on our experiences, “said Wilfred van der Donk (MMG), professor of chemistry and researcher at Howard Hughes Medical Institute.
The first breakthrough came in 2015, when the Nair lab in the Department of Biochemistry solved the crystal structure of a protein containing LanC in bacteria. The protein was linked to another enzyme called kinase, which changes proteins by adding a phosphate group. Inspired by this discovery, the researchers tested whether LanCL proteins also bind to kinases in eukaryotic cells. “We saw that they were able to bind to many kinases, including AKT and mTOR, and all of a sudden the pieces of the puzzle started to form an image,” van der Donk said.
The next piece was set up in collaboration with Benjamin Davis, professor of chemistry at the University of Oxford. The Davis group has shown that removing a particular phosphate group in kinases causes them to activate. Scientists had assumed that these transformed proteins would be inactive. Together, the Illinois and Oxford groups were able to show that LanCL adds glutathione to kinases with phosphate groups removed, after which the kinases deactivated. “We realized that when the LanCL proteins are missing, the cell has a big problem because there are active proteins floating around that need to be turned off,” said van der Donk.
The importance of these proteins became evident in mice that lacked them. “One third of mice lacking these enzymes die when they are between four and six months old. They die suddenly without getting sick and we still don’t understand why,” said Jie Chen (GNDP), professor of cell and development. biology.
The researchers want to understand the role of these proteins and to compile a complete list of all possible targets of LanCL. “When you have abnormal kinases it can cause all kinds of problems, including cancer. LanCL proteins eliminate these damaged kinases and it is possible that they also affect other proteins that we are not aware of. We need to relate their cellular functions to the results we’ve seen in mice, ”Chen said.
“This study is just the tip of the iceberg. As these proteins are found everywhere, you can also imagine their effects on raw materials and the future of agriculture,” said Satish Nair (MME / MMG) , head of the biochemistry department.
“This study was made possible by the persistence of our graduate students. Most of us would have dropped out a long time ago because education was going nowhere to begin with,” said Nair. “It also shows the importance of frontier research, where you just look around. While it’s risky, it’s great to see that there are rewards for the students who stick it out,” said van der Donk.