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7PX3

Structure of U5 snRNP assembly and recycling factor TSSC4 in complex with BRR2 and Jab1 domain of PRPF8

Summary for 7PX3
Entry DOI10.2210/pdb7px3/pdb
EMDB information13690
DescriptorU5 small nuclear ribonucleoprotein 200 kDa helicase, Pre-mRNA-processing-splicing factor 8, Protein TSSC4 (3 entities in total)
Functional Keywordsspliceosomal biogenesis, splicing
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains3
Total formula weight264166.35
Authors
Bergfort, A.,Kuropka, B.,Ilik, I.A.,Freund, C.,Aktas, T.,Hilal, T.,Weber, G.,Wahl, M.C. (deposition date: 2021-10-07, release date: 2022-01-26, Last modification date: 2024-07-17)
Primary citationBergfort, A.,Hilal, T.,Kuropka, B.,Ilik, I.A.,Weber, G.,Aktas, T.,Freund, C.,Wahl, M.C.
The intrinsically disordered TSSC4 protein acts as a helicase inhibitor, placeholder and multi-interaction coordinator during snRNP assembly and recycling.
Nucleic Acids Res., 50:2938-2958, 2022
Cited by
PubMed 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.
PubMed: 35188580
DOI: 10.1093/nar/gkac087
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.05 Å)
Structure validation

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