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  The intrinsically disordered TSSC4 protein acts as a helicase inhibitor, placeholder and multi-interaction coordinator during snRNP assembly and recycling

Bergfort, A., Hilal, T., Kuropka, B., Ilik, I. A., Weber, G., Aktas, T., et al. (2022). The intrinsically disordered TSSC4 protein acts as a helicase inhibitor, placeholder and multi-interaction coordinator during snRNP assembly and recycling. Nucleic Acids Research (London), 50(5), 2938-2958. doi:10.1093/nar/gkac087.

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Bergfort, Alexandra , Author
Hilal, Tarek , Author
Kuropka, Benno, Author
Ilik, Ibrahim Avsar1, Author              
Weber, Gert, Author
Aktas, Tugce1, Author              
Freund, Christian, Author
Wahl, Markus C. , Author
Affiliations:
1Quantitative RNA Biology (Tugce Aktas), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014184              

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 Abstract: Biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs) and their recycling after splicing require numerous assembly/recycling factors whose modes of action are often poorly understood. The intrinsically disordered TSSC4 protein has been identified as a nuclear-localized U5 snRNP and U4/U6-U5 tri-snRNP assembly/recycling factor, but how TSSC4's intrinsic disorder supports TSSC4 functions remains unknown. Using diverse interaction assays and cryogenic electron microscopy-based structural analysis, we show that TSSC4 employs four conserved, non-contiguous regions to bind the PRPF8 Jab1/MPN domain and the SNRNP200 helicase at functionally important sites. It thereby inhibits SNRNP200 helicase activity, spatially aligns the proteins, coordinates formation of a U5 sub-module and transiently blocks premature interaction of SNRNP200 with at least three other spliceosomal factors. Guided by the structure, we designed a TSSC4 variant that lacks stable binding to the PRPF8 Jab1/MPN domain or SNRNP200 in vitro. Comparative immunoprecipitation/mass spectrometry from HEK293 nuclear extract revealed distinct interaction profiles of wild type TSSC4 and the variant deficient in PRPF8/SNRNP200 binding with snRNP proteins, other spliceosomal proteins as well as snRNP assembly/recycling factors and chaperones. Our findings elucidate molecular strategies employed by an intrinsically disordered protein to promote snRNP assembly, and suggest multiple TSSC4-dependent stages during snRNP assembly/recycling.

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Language(s): eng - English
 Dates: 2022-01-262022-02-212022-03-21
 Publication Status: Published in print
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 Identifiers: DOI: 10.1093/nar/gkac087
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Title: Nucleic Acids Research (London)
  Other : Nucleic Acids Res
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 50 (5) Sequence Number: - Start / End Page: 2938 - 2958 Identifier: ISSN: 0305-1048
CoNE: https://pure.mpg.de/cone/journals/resource/110992357379342