8P25

Solution structure of a chimeric U2AF2 RRM2 / FUBP1 N-Box

Summary for 8P25

• Entry DOI: 10.2210/pdb8p25/pdb
• NMR Information: BMRB: 34816
• Descriptor: Splicing factor U2AF 65 kDa subunit,Far upstream element-binding protein 1 (1 entity in total)
• Functional Keywords: splicing, regulation, protein-protein interaction, rrm
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 16296.17

Authors

Hipp, C.,Sattler, M. (deposition date: 2023-05-14, release date: 2023-07-26, Last modification date: 2024-06-19)

Primary citation

Ebersberger, S.,Hipp, C.,Mulorz, M.M.,Buchbender, A.,Hubrich, D.,Kang, H.S.,Martinez-Lumbreras, S.,Kristofori, P.,Sutandy, F.X.R.,Llacsahuanga Allcca, L.,Schonfeld, J.,Bakisoglu, C.,Busch, A.,Hanel, H.,Tretow, K.,Welzel, M.,Di Liddo, A.,Mockel, M.M.,Zarnack, K.,Ebersberger, I.,Legewie, S.,Luck, K.,Sattler, M.,Konig, J.
FUBP1 is a general splicing factor facilitating 3' splice site recognition and splicing of long introns.
Mol.Cell, 83:2653-, 2023

PubMed Abstract: Splicing of pre-mRNAs critically contributes to gene regulation and proteome expansion in eukaryotes, but our understanding of the recognition and pairing of splice sites during spliceosome assembly lacks detail. Here, we identify the multidomain RNA-binding protein FUBP1 as a key splicing factor that binds to a hitherto unknown cis-regulatory motif. By collecting NMR, structural, and in vivo interaction data, we demonstrate that FUBP1 stabilizes U2AF2 and SF1, key components at the 3' splice site, through multivalent binding interfaces located within its disordered regions. Transcriptional profiling and kinetic modeling reveal that FUBP1 is required for efficient splicing of long introns, which is impaired in cancer patients harboring FUBP1 mutations. Notably, FUBP1 interacts with numerous U1 snRNP-associated proteins, suggesting a unique role for FUBP1 in splice site bridging for long introns. We propose a compelling model for 3' splice site recognition of long introns, which represent 80% of all human introns.

PubMed: 37506698
DOI: 10.1016/j.molcel.2023.07.002

Experimental method

SOLUTION NMR