snRNA catalysts in the spliceosome's ancient core

Abstract

The spliceosome, an assembly of snRNAs and proteins, catalyzes the removal of introns from premessenger RNAs. A new study identifies specific phosphates in the U2-U6 snRNA complex that position two catalytic metals. Remarkably, these correspond precisely to metal-binding phosphates in a homologous structure of Group II self-splicing introns, long proposed to be the ribozyme progenitor of spliceosome.

Figure 1. Catalysis of RNA Splicing

(A) Chemical steps catalyzed by the spliceosome and Group II ribozymes. (B) Proposed two-metal catalytic mechanism for RNA splicing (Steitz and Steitz, 1993). (C) Structure of the spliceosomal U2–U6 complex. Attack of the branchpoint adenosine (red arrow) on the 5' exon-intron junction is shown. (D) Comparison of active sites of a Group II ribozyme and the spliceosome. Left: Model for coordination of catalytic divalent cations in a Group II intron from Oceanobacillus iheyensis (Marcia and Pyle, 2013). Dotted lines indicate bonds with backbone phosphates inferred from high-resolution X-ray crystal structures. Right: Catalytic divalent cations positioned by the U2–U6 complex in the splceosome (Fica et al., 2013). Dark blue dotted lines indicate bonds with oxygen atoms identified by metal rescue experiments. Light blue dotted line indicates a proposed bond based on a defect in splicing produced by phosphorothioate substitution in U6.