Decrypting the Information Exchange Pathways across the Spliceosome Machinery

Intron
splicing of a nascent mRNA 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 accurate
directing of the compositional and conformational readjustments necessary
to achieve high splicing fidelity. Here, molecular dynamics (MD) simulations
of an 800 000 atom model of SPL C complex from yeast Saccharomyces 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 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 findings provide fundamental advances into mechanistic aspects
of SPL, providing a conceptual basis for controlling the SPL via small-molecule
modulators able to tackle splicing-associated diseases by altering/obstructing
information-exchange paths.