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Mechanism of protein-guided folding of the active site U2/U6 RNA during spliceosome activation.

Townsend C, Leelaram MN, Agafonov DE, Dybkov O, Will CL, Bertram K, Urlaub H, Kastner B, Stark H, Lührmann R
Science 370 (2020)
Related entries: 7aav, 7abf, 7abg, 7abh

Cited: 30 times
EuropePMC logo PMID: 33243851

Abstract

Spliceosome activation involves extensive protein and RNA rearrangements that lead to formation of a catalytically active U2/U6 RNA structure. At present, little is known about the assembly pathway of the latter and the mechanism whereby proteins aid its proper folding. Here, we report the cryo-electron microscopy structures of two human, activated spliceosome precursors (that is, pre-Bact complexes) at core resolutions of 3.9 and 4.2 angstroms. These structures elucidate the order of the numerous protein exchanges that occur during activation, the mutually exclusive interactions that ensure the correct order of ribonucleoprotein rearrangements needed to form the U2/U6 catalytic RNA, and the stepwise folding pathway of the latter. Structural comparisons with mature Bact complexes reveal the molecular mechanism whereby a conformational change in the scaffold protein PRP8 facilitates final three-dimensional folding of the U2/U6 catalytic RNA.

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  2. A genetic screen in C. elegans reveals roles for KIN17 and PRCC in maintaining 5' splice site identity. Suzuki JMNGL, Osterhoudt K, Cartwright-Acar CH, Gomez DR, Katzman S, Zahler AM. PLoS Genet 18 e1010028 (2022)


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  2. Structural studies of the spliceosome: Bridging the gaps. Tholen J, Galej WP. Curr Opin Struct Biol 77 102461 (2022)
  3. Cytogenetic and Genetic Abnormalities with Diagnostic Value in Myelodysplastic Syndromes (MDS): Focus on the Pre-Messenger RNA Splicing Process. Douet-Guilbert N, Soubise B, Bernard DG, Troadec MB. Diagnostics (Basel) 12 1658 (2022)
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  5. Zinc finger structure determination by NMR: Why zinc fingers can be a handful. Neuhaus D. Prog Nucl Magn Reson Spectrosc 130-131 62-105 (2022)
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  9. The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability. Idrissou M, Maréchal A. Cancers (Basel) 14 878 (2022)

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  2. Nopp140-chaperoned 2'-O-methylation of small nuclear RNAs in Cajal bodies ensures splicing fidelity. Bizarro J, Deryusheva S, Wacheul L, Gupta V, Ernst FGM, Lafontaine DLJ, Gall JG, Meier UT. Genes Dev 35 1123-1141 (2021)
  3. Saccharomyces cerevisiae Ecm2 Modulates the Catalytic Steps of pre-mRNA Splicing. van der Feltz C, Nikolai B, Schneider C, Paulson JC, Fu X, Hoskins AA. RNA rna.077727.120 (2021)
  4. A multi-factor trafficking site on the spliceosome remodeling enzyme BRR2 recruits C9ORF78 to regulate alternative splicing. Bergfort A, Preußner M, Kuropka B, Ilik İA, Hilal T, Weber G, Freund C, Aktaş T, Heyd F, Wahl MC. Nat Commun 13 1132 (2022)
  5. A forward genetic screen in C. elegans identifies conserved residues of spliceosomal proteins PRP8 and SNRNP200/BRR2 with a role in maintaining 5' splice site identity. Cartwright-Acar CH, Osterhoudt K, Suzuki JMNGL, Gomez DR, Katzman S, Zahler AM. Nucleic Acids Res 50 11834-11857 (2022)
  6. A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration. Meng D, Zheng Q, Zhang X, Piao X, Luo L, Jia Y. Protein Cell 14 318-336 (2023)
  7. A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing. El Fatimy R, Zhang Y, Deforzh E, Ramadas M, Saravanan H, Wei Z, Rabinovsky R, Teplyuk NM, Uhlmann EJ, Krichevsky AM. Mol Cancer 21 17 (2022)
  8. An ATP-independent role for Prp16 in promoting aberrant splicing. Chung CS, Wai HL, Kao CY, Cheng SC. Nucleic Acids Res 51 10815-10828 (2023)
  9. CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1. Hluchý M, Gajdušková P, Ruiz de Los Mozos I, Rájecký M, Kluge M, Berger BT, Slabá Z, Potěšil D, Weiß E, Ule J, Zdráhal Z, Knapp S, Paruch K, Friedel CC, Blazek D. Nature 609 829-834 (2022)
  10. Coupling of spliceosome complexity to intron diversity. Sales-Lee J, Perry DS, Bowser BA, Diedrich JK, Rao B, Beusch I, Yates JR, Roy SW, Madhani HD. Curr Biol 31 4898-4910.e4 (2021)
  11. Cross-linking mass spectrometry discovers, evaluates, and corroborates structures and protein-protein interactions in the human cell. Bartolec TK, Vázquez-Campos X, Norman A, Luong C, Johnson M, Payne RJ, Wilkins MR, Mackay JP, Low JKK. Proc Natl Acad Sci U S A 120 e2219418120 (2023)
  12. Identification of transient intermediates during spliceosome activation by single molecule fluorescence microscopy. Fu X, Kaur H, Rodgers ML, Montemayor EJ, Butcher SE, Hoskins AA. Proc Natl Acad Sci U S A 119 e2206815119 (2022)
  13. Quantitative prediction of variant effects on alternative splicing in MAPT using endogenous pre-messenger RNA structure probing. Kumar J, Lackey L, Waldern JM, Dey A, Mustoe AM, Weeks KM, Mathews DH, Laederach A. Elife 11 e73888 (2022)
  14. Regulation of 3' splice site selection after step 1 of splicing by spliceosomal C* proteins. Dybkov O, Preußner M, El Ayoubi L, Feng VY, Harnisch C, Merz K, Leupold P, Yudichev P, Agafonov DE, Will CL, Girard C, Dienemann C, Urlaub H, Kastner B, Heyd F, Lührmann R. Sci Adv 9 eadf1785 (2023)
  15. Structural and functional investigation of the human snRNP assembly factor AAR2 in complex with the RNase H-like domain of PRPF8. Preussner M, Santos KF, Alles J, Heroven C, Heyd F, Wahl MC, Weber G. Acta Crystallogr D Struct Biol 78 1373-1383 (2022)
  16. Structural basis for the interaction between the first SURP domain of the SF3A1 subunit in U2 snRNP and the human splicing factor SF1. Nameki N, Takizawa M, Suzuki T, Tani S, Kobayashi N, Sakamoto T, Muto Y, Kuwasako K. Protein Sci 31 e4437 (2022)
  17. U2 snRNA structure is influenced by SF3A and SF3B proteins but not by SF3B inhibitors. Urabe VK, Stevers M, Ghosh AK, Jurica MS. PLoS One 16 e0258551 (2021)
  18. UTP11 promotes the growth of hepatocellular carcinoma by enhancing the mRNA stability of Oct4. Chen Y, Zhang X, Zhang M, Fan W, Lin Y, Li G. BMC Cancer 24 93 (2024)
  19. Yeast U6 snRNA made by RNA polymerase II is less stable but functional. Lipinski KA, Chi J, Chen X, Hoskins AA, Brow DA. RNA 28 1606-1620 (2022)


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