Cryo-EM structure of a pre-catalytic human spliceosome primed for activation

• Autores: Karl Bertram, Dmitry E. Agafonov, Olexandr Dybkov, David Haselbach
• Localización: Cell, ISSN 0092-8674, Vol. 170, Nº. 4, 2017, págs. 701-713
• Idioma: inglés
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• Resumen

  • Little is known about the spliceosome’s structure before its extensive remodeling into a catalytically active complex. Here, we report a 3D cryo-EM structure of a pre-catalytic human spliceosomal B complex. The U2 snRNP-containing head domain is connected to the B complex main body via three main bridges. U4/U6.U5 tri-snRNP proteins, which are located in the main body, undergo significant rearrangements during tri-snRNP integration into the B complex. These include formation of a partially closed Prp8 conformation that creates, together with Dim1, a 5′ splice site (ss) binding pocket, displacement of Sad1, and rearrangement of Brr2 such that it contacts its U4/U6 substrate and is poised for the subsequent spliceosome activation step. The molecular organization of several B-specific proteins suggests that they are involved in negatively regulating Brr2, positioning the U6/5′ss helix, and stabilizing the B complex structure. Our results indicate significant differences between the early activation phase of human and yeast spliceosomes.