Mechanism of protein-guided folding of the active site U2/U6 RNA during spliceosome activation

Spliceosome activation involves extensive protein and RNA rearrangements that lead to formation of a catalytically active U2/U6 RNA structure. At present, little is known about the assembly pathway of the latter and the mechanism whereby proteins aid its proper folding. Here, we report the cryo-elec...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2020-12, Vol.370 (6523)
Main Authors: Townsend, Cole, Leelaram, Majety N, Agafonov, Dmitry E, Dybkov, Olexandr, Will, Cindy L, Bertram, Karl, Urlaub, Henning, Kastner, Berthold, Stark, Holger, Lührmann, Reinhard
Format: Article
Language:English
Subjects:
Assembly
Binding sites
Catalytic Domain
Cryoelectron Microscopy
Electron microscopy
Folding
Humans
Intermediates
Kinases
Microscopy
Molecular structure
mRNA
Networks
Precursors
Protein Conformation
Protein folding
Proteins
Ribonucleoproteins (U2 small nuclear)
RNA Folding
RNA Splicing
RNA, Catalytic - chemistry
RNA, Small Nuclear - chemistry
RNA, Small Nuclear - genetics
RNA-Binding Proteins - chemistry
Scaffolds
snRNA
Spliceosomes - chemistry
Spliceosomes - genetics
Splicing
Transmission electron microscopy
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Summary:Spliceosome activation involves extensive protein and RNA rearrangements that lead to formation of a catalytically active U2/U6 RNA structure. At present, little is known about the assembly pathway of the latter and the mechanism whereby proteins aid its proper folding. Here, we report the cryo-electron microscopy structures of two human, activated spliceosome precursors (that is, pre-B complexes) at core resolutions of 3.9 and 4.2 angstroms. These structures elucidate the order of the numerous protein exchanges that occur during activation, the mutually exclusive interactions that ensure the correct order of ribonucleoprotein rearrangements needed to form the U2/U6 catalytic RNA, and the stepwise folding pathway of the latter. Structural comparisons with mature B complexes reveal the molecular mechanism whereby a conformational change in the scaffold protein PRP8 facilitates final three-dimensional folding of the U2/U6 catalytic RNA.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abc3753