Molecular Mechanisms of pre-mRNA Splicing through Structural Biology of the Spliceosome (2019)

Precursor messenger RNA (pre-mRNA) splicing is executed by the spliceosome.

the spliceosome is a protein-directed metalloribozyme.

Precursor messenger RNA (pre-mRNA) splicing, discovered 40 years ago,  is executed by a multi-megaDalton, ribonucleoprotein (RNP) complex known as the spliceosome

The assembled spliceosome sequentially assumes eight different compositional states during each cycle of the splicing reaction

The available structural evidence proves the notion that the spliceosome is a metalloribozyme.

The protein components in each spliceosome can be divided into four distinct groups:

    1. the structural proteins,

 

  1. the splicing factors,
  2. the RNA-dependent ATPase/helicases,
  3. and other regulatory proteins.

The structural proteins sustain the splicing active site conformation, support the overall characteristic appearance of the spliceosome, and provide the elasticity that is needed for the splicing reaction.

splicing factors facilitate assembly and activation of the spliceosome and assist the two steps of transesterification.

The ATPase/helicases remodel the spliceosomal complexes to allow flux of the splicing factors and other proteins and RNA elements.

The other regulatory proteins modulate the splicing of pre-mRNA and will be briefly discussed in a later section.

 Importantly, the structure of the pre-B complex remains elusive. Consequently, we are yet to piece together the assembly process of the spliceosome.

The static structural images of the various spliceosomal complexes provide a physical basis for understanding the functions of the spliceosome. But these structures alone fail to answer some of the important mechanistic questions.

At this resolution, water molecules and the metal ions are yet to be conclusively identified. Improved resolution may also allow conclusive identification of posttranslational protein modifications and small-molecule ligands that target the various spliceosomal proteins.