wgalej [at] embl.fr
In eukaryotes, genetic information in protein-coding genes is dispersed in the form of short fragments (exons), which are punctuated with non-coding segments known as introns. Introns are removed from precursors of messenger RNAs (pre-mRNA) in a reaction catalysed by a multi-megadalton RNA–protein complex – the spliceosome. More than 100 proteins and five small nuclear RNAs (snRNAs) are involved in orchestrating this process. Among them, five small nuclear ribonucleoprotein particles (U1, U2, U4/U6, and U5 snRNPs) are the major building blocks of the splicing machinery. Recent technological advances in cryo-electron microscopy (cryo-EM) have allowed determination of high-resolution structures for nearly all yeast spliceosome assembly intermediates, providing unprecedented mechanistic insights into spliceosome assembly, activation, and catalysis.
Our group investigates three major problems related to the pre-mRNA splicing:
Our vision and approach
Mechanistic understanding of biological processes requires structural information on multiple scales. Research in my group employs cutting-edge structural biology technologies in investigating macromolecular complexes involved in the expression of the genetic information. By combining single particle electron cryo-microscopy (cryo-EM) with cell biology and biochemical and biophysical approaches, we aim to understand the inner workings of the large, multi-subunit RNA-protein complexes, involved in pre-mRNA splicing, snRNPs biogenesis and the 3’-end processing. These fundamentally important cellular processes are relevant to human health and their mechanistic understanding is of a critical importance for both, basic and applied research.
We employ modern genome engineering technologies and biochemical reconstitution methods with state-of-the-art electron microscopy approaches in order to visualise dynamic and flexible protein complexes. With a strong focus on biological problems, we aim to push the resolution limits and investigate ever more complex and dynamic machineries. In the fast-changing field of structural biology, we remain flexible and endorse new methodological developments in pursuing our biology- oriented research questions. As such, for our future goals we aspire to take advantage the newly emerging in situ structural biology methodologies and deep learning approaches to facilitate our progress.