7qtt
Structural organization of a late activated human spliceosome (Baqr, core region)
Structural highlights
FunctionSF3B3_HUMAN Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron. Publication Abstract from PubMedPre-mRNA splicing follows a pathway driven by ATP-dependent RNA helicases. A crucial event of the splicing pathway is the catalytic activation, which takes place at the transition between the activated B(act) and the branching-competent B(*) spliceosomes. Catalytic activation occurs through an ATP-dependent remodelling mediated by the helicase PRP2 (also known as DHX16)(1-3). However, because PRP2 is observed only at the periphery of spliceosomes(3-5), its function has remained elusive. Here we show that catalytic activation occurs in two ATP-dependent stages driven by two helicases: PRP2 and Aquarius. The role of Aquarius in splicing has been enigmatic(6,7). Here the inactivation of Aquarius leads to the stalling of a spliceosome intermediate-the B(AQR) complex-found halfway through the catalytic activation process. The cryogenic electron microscopy structure of B(AQR) reveals how PRP2 and Aquarius remodel B(act) and B(AQR), respectively. Notably, PRP2 translocates along the intron while it strips away the RES complex, opens the SF3B1 clamp and unfastens the branch helix. Translocation terminates six nucleotides downstream of the branch site through an assembly of PPIL4, SKIP and the amino-terminal domain of PRP2. Finally, Aquarius enables the dissociation of PRP2, plus the SF3A and SF3B complexes, which promotes the relocation of the branch duplex for catalysis. This work elucidates catalytic activation in human splicing, reveals how a DEAH helicase operates and provides a paradigm for how helicases can coordinate their activities. Structural basis of catalytic activation in human splicing.,Schmitzova J, Cretu C, Dienemann C, Urlaub H, Pena V Nature. 2023 May;617(7962):842-850. doi: 10.1038/s41586-023-06049-w. Epub 2023 , May 10. PMID:37165190[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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