Oligomerization of RNA Binding Proteins: Mechanism Unveiled

Oligomerization of RNA Binding Proteins: Mechanism Unveiled

“Why does my protein make jelly and how is it related to neurodegeneration? “Jakub Wojciechowski

At Sano Centre for Computational Medicine, we track breakthroughs in computational medicine, including research on mechanisms on protein aggreagation. The new article “Mechanism of ribonucleoprotein low complexity domain molecule oligomerization: Experimental investigations and theoretical modeling” by Paulina Żeliszewska, Pooja Shah, Kamil Rakowski, Jakub W. Wojciechowski (from our Sano team), Aleksandra Wosztyl, Anna Kluza, Aneta Michna, Zbigniew Adamczyk, and Anna Bratek-Skicki sheds light on a key challenge.

Problem: Unknown Oligomerization Mechanism

Nucleation of RNA-binding proteins is the first step in forming functional RNA-protein complexes (RNPs) that regulate RNA metabolism. But sometimes things can go wrong. Mutations in such protein can lead to severe neurodegenerative disorders like Amyotrophic lateral sclerosis and other forms of dementia. This study focuses on the low complexity domain (LCD) of heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) – a key player in RNA metabolism – whose oligomerization mechanism was poorly understood.

Solution: Experiments and Modeling

The authors combined experimental and theoretical techniques to better understand early stages of hnRNPA2 LCD aggregation in different ionic strengths and pH. They developed a new method of studying oligomerization stage using techniques adopted from material science and chemical engineering. Experiments were supported by Molecular dynamics modeling which provided atomic-level insight into pH driven conformational changes and their role in oligomerization.

Significance for Science and Medicine

Beyond basic research contributions, the results enabled development of an effective method for quantifying oligomerization kinetics in unstable protein solutions. The work highlights the role of computational modeling in understanding protein pathologies, aligning with Sano’s mission in personalized medicine.