Protein-mapping technique could pave the way for new drugs

Proteins were tracked in developing zebrafish

A novel way of detecting particular proteins that are implicated in a range of diseases could lead to new drug targets.

The technique could also deepen scientists’ understanding of embryonic development, as the proteins are also active during this early stage.

Proteins are essential for many of the functions carried out in the body. They are coded by genetic information in our cells, but after formation they are often modified so that they can perform their particular function. For example, they may be folded or other molecules may be added to them.

One of these types of additional molecules, the lipids, makes proteins much more difficult to detect. Lipid-modified proteins are implicated in infection and diseases such as cancer, making them an important target for new drugs.

For example, some lipid-modified proteins in humans act against viruses, but certain viruses can disrupt the process of proteins becoming modified in this way. Understanding how they do this could lead to molecules designed to block the virus’ interference.

The new method identifies and quantifies proteins modified by lipids in any organism, including humans and pathogens like viruses and bacteria.

By creating a reagent that sticks to the lipids of modified proteins, making them easier to detect, a team led by researchers at Imperial College London were able to identify a wide range of lipid-modified proteins. The technique is faster and more effective than previous methods, allowing them to identify nearly 100 of these proteins in human cells.

Characterising the activity of lipid-modified proteins and their associated enzymes in both humans and pathogens is an important factor in fighting disease. “We now have an excellent tool that gives us direct proof of lipid modifications happening in important proteins. This allows us to look at these proteins all together, and to quantify their behaviour,” said co-lead author Dr Remigiusz Serwa from the Department of Chemistry at Imperial.

Previously, the team identified an enzyme that causes a particular lipid-modification in the parasites behind the tropical diseases malaria and leishmaniasis. Blocking the activity of the enzyme, and preventing the modification, caused the parasites to shut down and eventually die.

Tracking development

In the new study, they were also able to characterise lipid-modified proteins in a complex living organism for the first time. They tracked the emergence of lipid-modified proteins through the different stages of development in a zebrafish embryo.

“For the first time, we can see how this modification responds in more than 50 different proteins as the animal takes shape and develops organs, giving an entirely novel perspective on vertebrate development,” said Professor Ed Tate from the Department of Chemistry at Imperial.

It also opens up the possibility of using zebrafish as a model to study lipid-modified proteins in disease. Quantifying the levels of proteins quickly will allow researchers to track the actions of potential new drugs designed to block activity and prevent modifications.

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'Multifunctional Reagents for Quantitative Proteome-Wide Analysis of Protein Modification in Human Cells and Dynamic Profiling of Protein Lipidation During Vertebrate Development' by M Broncel, RA Serwa, P Ciepla, E Krause, MJ Dallman, AI Magee and EW Tate is published in Angewandte Chemie.