Structural Insights into Nuclear pre-mRNA Splicing in Higher Eukaryotes
The spliceosome is a highly complex, dynamic ribonucleoprotein molecular machine that undergoes numerous structural and compositional rearrangements that lead to the formation of its active site. Recent advances in cyroelectron microscopy (cryo-EM) have provided a plethora of near-atomic structural information about the inner workings of the spliceosome. Aided by previous biochemical, structural, and functional studies, cryo-EM has confirmed or provided a structural basis for most of the prevailing models of spliceosome function, but at the same time allowed novel insights into splicing catalysis and the intriguing dynamics of the spliceosome. The mechanism of pre-mRNA splicing is highly conserved between humans and yeast, but the compositional dynamics and ribonucleoprotein (RNP) remodeling of the human spliceosome are more complex. Here, we summarize recent advances in our understanding of the molecular architecture of the human spliceosome, highlighting differences between the human and yeast splicing machineries. Outline 1 Introduction 2 Structure of human spliceosomal snRNPs 3 Structure of the precatalytic B complex 4 Structure of the activated (B act ) spliceosome 5 Structural basis of PRP2-mediated catalytic activation 6 Structural consequences of SF3B1 cancerrelated mutations 7 Insights into the function of PPIases and IBC proteins during splicing 8 Analysis of the conformational dynamics of hB act 9 Structure of human C and C * complexes 10 Insights into the mechanism of action of spliceosomal helicases 11 Large-scale movements of spliceosomal components 12 Future directions