Sagar Bhogaraju The importance of molecular tags for protein activity

Molecular “tags” on proteins 

The diversity of proteins allows them to participate in all key events of cellular life, such as metabolism, structural maintenance, and communication within and outside the cell. To do this, their structure can adapt, in particular through the addition of chemical modifications that occur after their production. 

Among these modifications, the addition of molecular “labels”, such as ubiquitin, plays a key role. Ubiquitin is a small protein that can be attached to other proteins by proteins called ligases. This addition can then direct the fate and function of the protein: it can serve as a signal for cellular communication or instruct the cell to destroy the modified protein.

Healthy or cancerous: the importance of ubiquitin 

Ubiquitin and the ligases that attach it to proteins are essential for cells to function properly. Sagar Bhogaraju is interested in one type of ligase in particular, RING ubiquitin ligases, whose deregulation is involved in the development of certain cancers. Factors called MAGE, which are present in large quantities in cancer cells, interact with RING ligases and modify their activity, altering the ubiquitination and degradation of proteins that are key to the development of cancer. 

Despite their importance for cell signalling and the therapeutic potential of the ubiquitination system, very few of the target proteins of RING ligases are known to date. The difficulty lies in the fact that the activity of a ubiquitin ligase in attaching ubiquitin to a target protein is extremely rapid and reversible, complicating the task of researchers attempting to capture their targets.

The ubiquitination atlas for developing new therapies 

Thanks to Impulscience, Sagar Bhogaraju and his team will be able to explore the world of RING ligases, from their regulation by MAGE proteins to the discovery of their targets. To overcome technical obstacles, they recently developed a new experimental method called Ub-POD, which allows proteins to be “labelled” at the precise moment they are ubiquitinated, directly in cells. 

The first stage of this project will focus on identifying target proteins of 21 RING ligases involved in diseases such as cancer and certain brain development disorders. The team will also focus on the regulation of RING ligase activity in the context of cancer, and will use the Ub-POD method to identify ubiquitinated proteins in the brain in the context of cocaine addiction. This project will provide a better understanding of the mechanisms involved in ubiquitination and pave the way for new therapeutic approaches targeting this fundamental system.