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Revealing the changing shapes of proteins


Photograph of Paola Picotti


Heidelberg, 5 June 2019 – Paola Picotti, one of two recipients of the EMBO Gold Medal 2019, talked to Rosemary Wilson about her work on her work on protein–small molecule interactions and protein aggregation, her fascination with complex problems and the need to feel excited by a topic.  


What motivated you to go into scientific research?


When I was young, I felt a sense of unease when I did not understand something, but also excitement once I had the chance to dig down to where things were puzzling. This fascination for complex problems attracted me to science and research.


When did you first become fascinated by proteins?


I remember the moment very clearly. In a lecture during my undergraduate studies, our biochemistry professor showed us an image of a gigantic protein structure. It was the ATP synthase, a protein complex crucial for the functioning of our cells. I was fascinated. I thought it was beautiful, complex and mysterious. I remember thinking, ‘wow, I could spend the rest of my life studying how this, and other proteins work’. And I’m very lucky that this seems to have happened! 


You developed an approach to analyse structural changes in proteins. What makes the limited proteolysis coupled to mass spectrometry, or LiP-MS, method so powerful?


Protein structural changes are largely studied in vitro, for which you must first identify a specific protein for analysis. The LiP-MS method, however, is a biochemical and mass-spectrometric approach that can identify proteins that undergo a structural change directly from a complex biological sample. It can be used to systematically identify proteins that change conformation, unfold, or aggregate in cells treated in different ways. Since binding of a small molecule also affects the structure of a protein, the approach can be used to identify interactions between proteins and small molecules, including identification of drug targets, and binding sites. 


You used the LiP-MS method to tackle some key topics, such as protein stability and metabolite–protein interactions in their native environments. What did these studies reveal?


In the first study we looked at the thermal denaturation profiles of around 8000 proteins from several species. We found that when cells die of heat, a few proteins with very crucial roles are lost due to denaturation. Proteins in thermophilic bacteria, however, undergo these changes only at higher temperature and are less prone to aggregation. The results contributed to our understanding of why some cells survive high temperatures and others don’t. 

For the second study we produced a map of 1700 metabolite–protein interactions; 1400 of which were new. These interactions are functionally very relevant, since a metabolite can change the functional state of a protein completely, for example turning an enzyme on or off. This map provided several new insights, for example, that the catalytic sites of some enzymes are promiscuous and can bind more metabolites than previously thought.


What research is your lab focussing on now?


My lab studies the molecular basis of protein aggregation diseases such as Parkinson’s disease. These diseases are characterised by proteins that undergo a structural change, making them prone to form aggregates. We are currently studying the structures of aggregates and aggregation intermediates directly in cellular extracts and tissues. And we are asking whether altered protein structures in biological fluids such as cerebrospinal fluid can be used as a new class of biomarkers for Parkinson’s disease. 


What advice do you pass on to your students?


Firstly, I feel it is important that students use their Ph.D. to learn how to think critically and independently. Secondly, they should pick a topic that excites them, and then dig in. If there is no excitement, then there won’t be enough motivation to keep going. We all know this! 

And finally, I feel it is important that students develop a positive attitude towards science and scientific results. Sometimes a failed experiment contains useful information, and sometimes a failed hypothesis can mean an even more exciting discovery. 


How do you support others in balancing family and work life?


I believe it is possible to be a dedicated parent and an engaged scientist and I am passionate about supporting others in reconciling family and work life. That’s why I started a project to finance emergency childcare in my group. Especially in the winter, young children can often be sick, and this can really affect productivity. I am a mother of two and I know that this can be challenging. Maybe the support we provide does not completely solve the issue, but I hope it contributes to creating a supportive work atmosphere.


What does receiving the EMBO Gold Medal mean to you?


It is wonderful to get such recognition, and I accept the award on behalf of all my group members, past and present, who contributed to this work. I also feel very honoured to receive it alongside Madan Babu, whose work on intrinsically disordered proteins inspired parts of our work. 




Read the interview with the other 2019 Gold Medal recipient, Madan Babu, here



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Tilmann KiesslingTilmann Kiessling
Head, Communications
T. + 49 160 9019 3839