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Science. 2019 Apr 11. pii: eaax3289. doi: 10.1126/science.aax3289. [Epub ahead of print]

Mechanism of 5' splice site transfer for human spliceosome activation.

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MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.


The prespliceosome, comprising U1 and U2 snRNPs bound to the pre-mRNA 5' splice site (5'SS) and branch point sequence, associates with the U4/U6.U5 tri-snRNP to form the fully-assembled precatalytic pre-B spliceosome. Here, we report cryo-EM structures of the human pre-B complex captured before U1 snRNP dissociation at 3.3 Å core resolution, and the human tri-snRNP at 2.9 Å resolution. U1 snRNP inserts the 5'SS-U1 snRNA helix between the two RecA domains of the Prp28 DEAD-box helicase. ATP-dependent closure of the Prp28 RecA domains releases the 5'SS to pair with the nearby U6 ACAGAGA-box sequence presented as a mobile loop. The structures suggest that formation of the 5'SS-ACAGAGA helix triggers remodeling of an intricate protein-RNA network to induce Brr2 helicase relocation to its loading sequence in U4 snRNA, enabling Brr2 to unwind the U4/U6 snRNA duplex to allow U6 snRNA to form the catalytic center of the spliceosome.


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