Decrypting the information exchange pathways across the spliceosome machinery.

Intron splicing of a nascent messenger RNA transcript by spliceosome (SPL) is a hallmark of gene regulation in eukaryotes. SPL is a majestic molecular machine composed of an entangled network of proteins and RNAs that meticulously promotes intron splicing through the formation of eight intermediate complexes. Cross-communication among the critical distal proteins of the SPL assembly is pivotal for fast and accurately directing the compositional and conformational readjustments necessary to achieve high splicing fidelity. Here, Molecular Dynamics (MD) simulations of an 800,000 atoms model of SPL C complex from yeast S. cerevisiae and community network analysis enabled us to decrypt the complexity of this huge molecular machine, by identifying the key channels of information transfer across the long distances separating key protein-components. The reported study represents an unprecedented attempt in dissecting cross-communication pathways within one of the most complex machines of eukaryotic cells, supporting the critical role of Clf1 and Cwc2 splicing cofactors and specific domains of the Prp8 protein as signal conveyors for pre-mRNA maturation. Our outcomes provide fundamental advances into mechanistic aspects of SPL, providing a conceptual basis for controlling the SPL via small-molecules modulators able to tackle splicing-associated diseases by altering/obstructing these information-exchange paths.