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  Molecular architecture of the human 17S U2 snRNP

Zhang, Z., Will, C. L., Bertram, K., Dybkov, O., Hartmuth, K., Agafonov, D. E., et al. (2020). Molecular architecture of the human 17S U2 snRNP. Nature, 583(7815), 310-313. doi:10.1038/s41586-020-2344-3.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-1C12-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-1C1A-E
Genre: Journal Article

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 Creators:
Zhang, Z.1, Author              
Will, C. L.2, Author              
Bertram, K.1, Author              
Dybkov, O.2, Author              
Hartmuth, K.2, Author              
Agafonov, D. E.2, Author              
Hofele, R. V.3, Author              
Urlaub, H.3, Author              
Kastner, B.2, Author              
Lührmann, R.2, Author              
Stark, H.1, Author              
Affiliations:
1Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_2205645              
2Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              
3Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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Free keywords: Cryoelectron microscopy, RNA splicing
 Abstract: The U2 small nuclear ribonucleoprotein (snRNP) has an essential role in the selection of the precursor mRNA branch-site adenosine, the nucleophile for the first step of splicing1. Stable addition of U2 during early spliceosome formation requires the DEAD-box ATPase PRP52,3,4,5,6,7. Yeast U2 small nuclear RNA (snRNA) nucleotides that form base pairs with the branch site are initially sequestered in a branchpoint-interacting stem–loop (BSL)8, but whether the human U2 snRNA folds in a similar manner is unknown. The U2 SF3B1 protein, a common mutational target in haematopoietic cancers9, contains a HEAT domain (SF3B1HEAT) with an open conformation in isolated SF3b10, but a closed conformation in spliceosomes11, which is required for stable interaction between U2 and the branch site. Here we report a 3D cryo-electron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 Å and combine it with protein crosslinking data to determine the molecular architecture of this snRNP. Our structure reveals that SF3B1HEAT interacts with PRP5 and TAT-SF1, and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a BSL that is sandwiched between PRP5, TAT-SF1 and SF3B1HEAT. Thus, substantial remodelling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2–branch-site helix. Our studies provide a structural explanation of why TAT-SF1 must be displaced before the stable addition of U2 to the spliceosome, and identify RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.

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Language(s): eng - English
 Dates: 2020-06-032020-07-09
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41586-020-2344-3
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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 583 (7815) Sequence Number: - Start / End Page: 310 - 313 Identifier: -