Molecular Mechanisms of pre-mRNA Splicing through Structural Biology of the Spliceosome

Precursor messenger RNA ( pre-mRNA) splicing is executed by the spliceosome. In the past 3 years, cryoelectron microscopy (cryo-EM) structures have been elucidated for a majority of the yeast spliceosomal complexes and for a few human spliceosomes. During the splicing reaction, the dynamic spliceosome has an immobile core of about 20 protein and RNA components, which are organized around a conserved splicing active site. The divalent metal ions, coordinated by U6 small nuclear RNA (snRNA), catalyze the branching reaction and exon ligation. The spliceosome also contains a mobile but compositionally stable group of about 13 proteins and a portion of U2 snRNA, which facilitate substrate delivery into the splicing active site. The spliceosomal transitions are driven by the RNA-dependent ATPase/helicases, resulting in the recruitment and dissociation of specific splicing factors that enable the reaction. In summary, the spliceosome is a protein-directed metalloribozyme. Outline 1 Introduction 2 Structural studies of the spliceosome 3 Shared features of the spliceosomes 4 Spliceosome as a metalloribozyme 5 The role of the protein components 6 Recognition of the RNA elements 7 Choreography of the RNA and protein components 8 The human spliceosome 9 Conclusion