Protein Methylation

Methylation

Proteins, one of the major classes of biological molecules perform a multitude of tasks within our cells and bodies. To make sure they do the correct job at the right time, they are very tightly regulated. One method of regulation is through the addition of chemical groups to the protein - methylation is one of these, and is able to change how a protein interacts with other molecules, when the protein is made and when the protein is destroyed - as well as in sensing changes in the environment (such as glucose). There is still a lot to find out about how this modification works - including what proteins are affected by it, how it is regulated, and what pathways it is active in. In my research, I want to explore the role of protein methylation in cancer, with the aim of identifying the underlying biology and potential new treatment opportunities.

Enrichment

We use a technique called mass spectrometry to identify and quantify methylated proteins. This approach is very powerful, allowing the discovery and quantification of many proteins simultaneously. However, one difficulty is in identifying methylated proteins (peptides) that are in very low abundance. One way to circumvent that is to "enrich" for these proteins prior to analysis. This can be very difficult and many techniques are available, but for proteins containing lysine methylations, the available approaches do not work. In collaboration with Chemists at Imperial College and the CRICK, we are developing novel chemical probes to target lysine methylation for enrichment. This will be a real "game-changer" in the field, allowing unparalleled access to methylated proteins.

Disease

Protein methylation is key regulatory process of many disease-associated proteins, including cancer (oncogenes) and neurological disease. Cancer is a disease in which the regulation of cell-cycling breaks down and cells proliferate with little or no control. In 15% of all cancers, a gene called MTAP is deleted. This gene is important for preventing the toxic build-up of a small compound, MTA, which is ultimately converted into SAM - the molecule that donates a methyl-group for protein methylation. This results in a reduction in the cellular abundance of the compound required for all protein methylation. In many cancers, this causes a vulnerability to processes requiring protein methylation and it has been shown that in these cases, cells are sensitive to inhibition of some methyltransferases (e.g. PRMT5). I am interested in exploring the relationship between metabolomic changes arising from MTAP deletion in cancer and protein methylation. I hope to uncover specific pathways that are sensitive to chemical inhibition when MTAP is deleted as this will provide us with new cancer-specific therapeutic opportunities.