Cryo-EM snapshots of the human spliceosome reveal structural adaptions for splicing regulation

Abstract

Introns are excised from pre-messenger RNAs by the spliceosome, which produces mRNAs with continuous protein-coding information. In humans, most pre-mRNAs undergo alternative splicing to expand proteomic diversity. Cryo-electron microscopy (cryo-EM) structures of the yeast spliceosome elucidated how proteins stabilize and remodel an RNA-based active site to effect splicing catalysis. More recent cryo-EM snapshots of the human spliceosome reveal a complex protein scaffold and provide insights into the role of specific human proteins in modulating spliceosome activation, splice site positioning, and the ATPase-mediated dynamics of the active site. The emerging molecular picture highlights how, compared to its yeast counterpart, the human spliceosome has coopted additional protein factors to allow increased plasticity of splice site recognition and remodeling, and potentially to regulate alternative splicing.