ArticleProceedings of the National Academy of Sciences of the United States of America2016
Recognition of the 3' splice site RNA by the U2AF heterodimer involves a dynamic population shift.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 77 citations in OpenAlex.
- REAL-TIME VISUALIZATION OF SPLICEOSOME ASSEMBLY REVEALS BASIC PRINCIPLES OF 3' SPLICE SITE SELECTION.Research square · 2026Article
- Deployment of non-canonical splicing in tunicate genomes is mediated by divergent U2AF function and changing m6A modification in U1 and U6 snRNA.Nucleic acids research · 2026Article
- Review
- Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML.Cell reports. Medicine · 2026Article
- Genome-wide modulation of alternative splicing by a predicted alpha helix in U2AF2.Nucleic acids research · 2025Article
- Organism-Specific Sequence Motifs Link Ribosomal RNAs to Brain Disorders.Molecular biology and evolution · 2025Article
- Roquin exhibits opposing effects on RNA stem-loop stability through its two ROQ domain binding sites.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Tumor Antigens beyond the Human Exome.International journal of molecular sciences · 2024Review
- Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Analysis of the inter-domain orientation of tandem RRM domains with diverse linkers: connecting experimental with AlphaFold2 predicted models.NAR genomics and bioinformatics · 2024Article
- Exonic splicing code and coordination of divalent metals in proteins.Nucleic acids research · 2024Article
- Nuclear magnetic resonance/single molecule fluorescence combinations to study dynamic protein systems.Current opinion in structural biology · 2023Review
- Research Progress on the Structural and Functional Roles of hnRNPs in Muscle Development.Biomolecules · 2023Review
- Early Splicing Complexes and Human Disease.International journal of molecular sciences · 2023Review
- Article
- Reliability and accuracy of single-molecule FRET studies for characterization of structural dynamics and distances in proteins.Nature methods · 2023Article
- Deciphering the RRM-RNA recognition code: A computational analysis.PLoS computational biology · 2023Article
- Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing ofScience advances · 2022Article
- The dynamic, motile and deformative properties of RNA nanoparticles facilitate the third milestone of drug development.Advanced drug delivery reviews · 2022Review
- Pre-mRNA splicing factor U2AF2 recognizes distinct conformations of nucleotide variants at the center of the pre-mRNA splice site signal.Nucleic acids research · 2022Article
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9 authors at 7 institutions in 3 countries.
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Abstract
An essential early step in the assembly of human spliceosomes onto pre-mRNA involves the recognition of regulatory RNA cis elements in the 3' splice site by the U2 auxiliary factor (U2AF). The large (U2AF65) and small (U2AF35) subunits of the U2AF heterodimer contact the polypyrimidine tract (Py-tract) and the AG-dinucleotide, respectively. The tandem RNA recognition motif domains (RRM1,2) of U2AF65 adopt closed/inactive and open/active conformations in the free form and when bound to bona fide Py-tract RNA ligands. To investigate the molecular mechanism and dynamics of 3' splice site recognition by U2AF65 and the role of U2AF35 in the U2AF heterodimer, we have combined single-pair FRET and NMR experiments. In the absence of RNA, the RRM1,2 domain arrangement is highly dynamic on a submillisecond time scale, switching between closed and open conformations. The addition of Py-tract RNA ligands with increasing binding affinity (strength) gradually shifts the equilibrium toward an open conformation. Notably, the protein-RNA complex is rigid in the presence of a strong Py-tract but exhibits internal motion with weak Py-tracts. Surprisingly, the presence of U2AF35, whose UHM domain interacts with U2AF65 RRM1, increases the population of the open arrangement of U2AF65 RRM1,2 in the absence and presence of a weak Py-tract. These data indicate that the U2AF heterodimer promotes spliceosome assembly by a dynamic population shift toward the open conformation of U2AF65 to facilitate the recognition of weak Py-tracts at the 3' splice site. The structure and RNA binding of the heterodimer was unaffected by cancer-linked myelodysplastic syndrome mutants.
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