Molecular choreography of pre-mRNA splicing by the spliceosome (2019)

The spliceosome executes eukaryotic precursor messenger RNA (pre-mRNA) splicing to remove noncoding introns through two sequential transesterification reactions, branching and exon ligation.

The fidelity of this process is based on the recognition of the conserved sequences in the intron and dynamic compositional and structural rearrangement of this multi-megadalton machinery.

Since atomic visualization of the splicing active site in an endogenous Schizosaccharomyces pombe spliceosome in 2015, high-resolution cryoelectron microscopy (cryo-EM) structures of other spliceosome intermediates began to uncover the molecular mechanism.

Recent advances in the structural biology of the spliceosome make it clearer the mechanisms of its assembly, activation, disassembly and exon ligation.

Together, these discrete structural images give rise to a molecular choreography of the spliceosome.

Since visualization of the first atomic structure of an intact spliceosome in 2015, all eight major functional states of the fully assembled spliceosome from S. cerevisiae and all but one such states from human have been structurally characterized (Table 1).

The atomic structures of the pre-B, B, B^act, B*, C*, P, and ILS from S. cerevisiae recapitulate the process of spliceosome assembly, activation, catalysis, and disassembly.

This information, together with structures of other spliceosomal complexes, give rise to a molecular choreography of pre-mRNA splicing by the spliceosome.

Although many details remain to be elucidated through additional biochemical and biophysical studies, what we have already seen represents a remarkable achievement by cryo-EM in a fundamental area of biological research.