With the determination of the crystalline structure of the protein complex LAMTOR, scientists led by Lukas Huber also discovered the sensitive “Achilles’ heel” of the complex and would like to use this knowledge to advance the development of new therapeutic approaches in the future.
The protein complex LAMTOR was identified 15 years ago and, as we know, plays an important role in the development of cancer and metabolic diseases such as diabetes and metabolic syndrome by coordinating certain signalling pathways in the cell. It controls signal forwarding, such as MAPK and mTORC, which control growth, division, migration or self-destruction in a cell.
Already years ago, Lukas Huber and his team were able to show that the LAMTOR complex consists of seven known scaffolding and regulatory proteins. Using biomolecular crystallography, MUI scientists have now been able to clarify the three-dimensional structure of the protein complex in cooperation with ADSI. They recognized that one of the seven proteins (LAMTOR1) plays a central role and forms the clamp that holds the remaining components together and attaches the complex to the relevant cell structures.
The researchers then use these findings to use gene scissors to introduce mutations into the cells, which specifically altered the protein complex. It was found that the complex was ineffective and no mTORC signal transduction occurred when the LAMTOR 1 protein was severed at certain points.
The findings have attracted international attention and it will now be the aim to use the knowledge about this “Achilles’ heel” of the protein complex to research new therapeutic approaches. Together with ADSI, the development of new drugs is to be driven forward in the coming years, which will deactivate LAMTOR and thus prevent an overaction of the mTOR signaling pathway and subsequently the development of cancer and metabolic diseases.
Original paper: Crystal Structure of the Human Lysosomal mTORC1 Scaffold Complex and its Impact on Signaling. Mariana E.G. de Araujo, Andreas Naschberger, Barbara G. Fürnrohr, Taras Stasyk, Theresia Dunzendorfer-Matt, Stefan Lechner, Stefan Welti, Leopold Kremser, Giridhar Shivalingaiah, Martin Offterdinger, Herbert H. Lindner, Lukas A. Huber, Klaus Scheffzek. Science 21 Sep 2017.
Mypoint Medizinische Universität Innsbruck