Decoding Disorder: Researchers Unveil Secrets of Intrinsically Disordered Proteins
February 1, 2024Proteins, the building blocks of biology, have long been believed to adhere to a specific three-dimensional structure, critical for their functions. However, this understanding faces a challenge from intrinsically disordered proteins, constituting a third of all proteins, with shapes constantly in flux despite serving essential biological roles. In a groundbreaking study published in the journal Nature, researchers from the Department of Biology at the University of Copenhagen have cracked the code, revealing the behavior of approximately 28,000 disordered proteins within the human body.
Professor Kresten Lindorff-Larsen, director of the NNF centre, PRISM, where the research unfolded, expresses his fascination, “I have always been fascinated by intrinsically disordered proteins because they seem to defy most of the rules of how a protein should behave. For the first time, we have now been able to study the structure of all human disordered proteins and begun to provide order into this world of molecular disorder.”
The PRISM centre, dedicated to combining computational methods from biophysics and machine learning with cell biology, aims to decipher how genetic variants contribute to disease. However, the lack of knowledge about the appearance of most disordered proteins hindered their ability to understand the impact of gene mutations on disease.
Assistant Professor Giulio Tesei, a lead author, explains the breakthrough methodology, “Until recently, we examined the disordered proteins one-by-one, and it was essential to find a way to study them on a larger scale. We came up with an approach where we could use experimental measurements on disordered proteins to develop a computational model to predict their properties. Since this model is both accurate and fast, we can now look at them all.”
Notably, the study, co-led by bachelor student Anna Ida Trolle, defied the conventional practice of studying one or two proteins at a time. Trolle reflects on the ambitious endeavor, “When I started the project, I didn’t know that you typically just study one or two proteins at a time. So, when Giulio and Kresten suggested that I should study some 28,000 proteins, I fortunately didn’t realize how crazy an idea it was.”
The research marks a significant leap in understanding the language of disordered proteins, linking their molecular properties to biological functions and roles in diseases. The team’s innovative approach provides a comprehensive view of this molecular realm, shedding light on the intricate dynamics of proteins previously considered enigmatic.
Referfence:
Tesei, G., Trolle, A. I., Jonsson, N., Betz, J., Knudsen, F., Pesce, F., … & Lindorff-Larsen, K. (2024). Conformational ensembles of the human intrinsically disordered proteome. Bulletin of the American Physical Society.
