Max Perutz Lecture: Structural insights into the cascade of snRNP remodeling steps leading to the formation of a catalytically activated spliceosome - IN PERSON ONLY

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• Reinhard Lührmann, Max Planck Institute for Biophysical Chemistry
• Monday 24 March 2025, 11:00-12:00
• In person in the Max Perutz Lecture Theatre (CB2 0QH) .

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The spliceosome, which catalyzes the removal of introns from pre-mRNA molecules, forms anew on each pre-mRNA intron, through a pathway involving multiple, successive assembly intermediates. Early spliceosome formation involves the binding of the U1 and U2 snRNPs to the 5’ and 3’ ends of an intron, respectively, yielding the A complex. Recruitment of the U4/U5.U6 tri-snRNP leads to the formation of the pre-B complex, which is remodeled into the B complex. The pre-B to B transition, and the transformation of the pre-catalytic B complex into an activated (Bact) spliceosome, involves extensive protein exchanges and RNA rearrangements that lead to the formation of a catalytically active U2/U6 structure. Our cryo-EM structures of pre-B, B and several distinct pre-Bact assembly intermediates reveal an intricate cascade of highly coordinated structural changes during the activation phase of the human spliceosome. They also reveal unprecedented, large-scale translocations of proteins and entire RNP domains, with RNA helicases and kinases acting as driving forces. In addition, our studies reveal the molecular mechanism whereby formation of a catalytically active U2/U6 RNA network is facilitated by spliceosomal proteins, with a conformational change in the scaffold protein PRP8 playing a key role in facilitating its final 3D folding.

This talk is part of the MRC LMB Seminar Series series.

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