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  Structural insights into the roles of metazoan-specific splicing factors in the human step 1 spliceosome

Bertram, K., El Ayoubi, L., Dybkov, O., Agafonov, D., Will, C. L., Hartmuth, K., et al. (2020). Structural insights into the roles of metazoan-specific splicing factors in the human step 1 spliceosome. Molecular Cell, 80(1), 127-139.e6. doi:10.1016/j.molcel.2020.09.012.

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 Creators:
Bertram, K.1, Author              
El Ayoubi, L.2, Author              
Dybkov, O.3, Author              
Agafonov, D.3, Author              
Will, C. L.3, Author              
Hartmuth, K.3, Author              
Urlaub, H.4, Author              
Kastner, B.3, Author              
Stark, H.1, Author              
Lührmann, R.3, Author              
Affiliations:
1Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_2205645              
2Department of Cellular Biochemistry, MPl for Biophysical Chemistry, Max Planck Society, ou_578576              
3Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              
4Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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Free keywords: pre-mRNA splicing; human spliceosome; C complex; metazoan-specific splicing factors; cryo-EM; spliceosome structure; step 1 spliceosome
 Abstract: Human spliceosomes contain numerous proteins absent in yeast, whose functions remain largely unknown. Here we report a 3D cryo-EM structure of the human spliceosomal C complex at 3.4 Å core resolution and 4.5–5.7 Å at its periphery, and aided by protein crosslinking we determine its molecular architecture. Our structure provides additional insights into the spliceosome’s architecture between the catalytic steps of splicing, and how proteins aid formation of the spliceosome’s catalytically active RNP (ribonucleoprotein) conformation. It reveals the spatial organization of the metazoan-specific proteins PPWD1, WDR70, FRG1, and CIR1 in human C complexes, indicating they stabilize functionally important protein domains and RNA structures rearranged/repositioned during the Bact to C transition. Structural comparisons with human Bact, C∗, and P complexes reveal an intricate cascade of RNP rearrangements during splicing catalysis, with intermediate RNP conformations not found in yeast, and additionally elucidate the structural basis for the sequential recruitment of metazoan-specific spliceosomal proteins.

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Language(s): eng - English
 Dates: 2020-10-012020-10
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.molcel.2020.09.012
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Title: Molecular Cell
Source Genre: Journal
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Pages: - Volume / Issue: 80 (1) Sequence Number: - Start / End Page: 127 - 139.e6 Identifier: -