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bioRxiv · 10.1101/2024.09.13.612651

Structures of aberrant spliceosome intermediates on their way to disassembly

Soni, K.·Horvath, A.·Dybkov, O.·Schwan, M.·Trakansuebkul, S.·Flemming, D.·Wild, K.·Urlaub, H.·Fischer, T.·Sinning, I.
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Abstract

Intron removal during pre-mRNA splicing is of extraordinary complexity and its disruption causes a vast number of genetic diseases in humans1. While key steps of the canonical spliceosome cycle have been revealed by combined structure-function analyses2,3, structural information on an aberrant spliceosome committed to premature disassembly is not available. Here, we report two cryo-EM structures of post-Bact spliceosome intermediates from S. pombe primed for disassembly. We identify the DEAH-box helicase - G patch protein pair (Gih35-Gpl1, homologous to human DHX35-GPATCH1) and show how it maintains catalytic dormancy. In both structures, Gpl1 recognizes a remodeled active site introduced by an over-stabilization of the U5 loop I interaction with the 5 exon leading to a single nucleotide insertion at the 5splice site. Remodeling is communicated to the spliceosome surface and the Ntr1 complex that mediates disassembly is recruited. Our data pave the way for a targeted analysis of splicing quality control.

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Soni, K., Horvath, A., Dybkov, O., Schwan, M., Trakansuebkul, S., Flemming, D., Wild, K., Urlaub, H., Fischer, T., Sinning, I.. 2024-09-14. Structures of aberrant spliceosome intermediates on their way to disassembly. https://doi.org/10.1101/2024.09.13.612651

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