The human spliceosome and its complex catalytic elements on the move

The spliceosome is a macromolecular complex comprising over 35 proteins and 4 RNA molecules in its functional state. In eukaryotes, the spliceosome plays a critical role in regulating gene expression by facilitating mRNA maturation through a two-step catalytic process known as splicing.

Central to spliceosome function is the fine-tuned dynamics of catalytic elements at the active site, which ensures substrate recognition, catalysis, and splicing progression. However, our understanding of how specific protein cofactors – which are essential for spliceosome assembly – influence the dynamics of catalytic elements of the spliceosome remained so far limited due to the scarcity of high-resolution structural data. In this context, we seek access to PRACE resources to investigate – with an unprecedented atomistic resolution – the complex dynamics of spliceosome catalytic elements and the stepwise recruitment of protein cofactors.

Leveraging cutting-edge molecular dynamics simulations integrated with cryo-electron microscopy data, we aim to obtain atomistic insights into experimentally-validated spliceosome structural ensembles during various stages of catalysis. In an era where first-in-class FDA-approved splicing regulators have emerged as pivotal tools in resolving lethal human diseases, the results of this research project will likely be of great interest to a wide and interdisciplinary audience in the life sciences, including cellular and structural biologists, as well as drug designers across academia and private corporations.