9C7B

Crystal structure of R150H neurodevelopmental disease-associated U2AF2 variant

Summary for 9C7B

• Entry DOI: 10.2210/pdb9c7b/pdb
• Descriptor: Splicing factor U2AF 65 kDa subunit, DNA/RNA (5'-R(P*UP*U)-D(P*U)-R(P*UP*U)-D(P*(BRU))-R(P*CP*C)-3') (3 entities in total)
• Functional Keywords: protein-rna complex, rna splicing factor, rna recognition motif, polypyrimidine tract, rna binding protein-rna complex, rna binding protein-splicing complex, rna binding protein, rna binding protein-rna-dna complex, rna binding protein/rna/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 24667.58

Authors

Maji, D.,Jenkins, J.L.,Kielkopf, C.L. (deposition date: 2024-06-10, release date: 2024-10-02, Last modification date: 2024-10-30)

Primary citation

Maji, D.,Jenkins, J.L.,Boutz, P.L.,Kielkopf, C.L.
Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities and Interactions.
Biochemistry, 2024

PubMed Abstract: mutations affecting the pre-mRNA splicing factor U2AF2 are associated with developmental delays and intellectual disabilities, yet the molecular basis is unknown. Here, we demonstrated by fluorescence anisotropy RNA binding assays that recurrent missense mutants (Arg149Trp, Arg150His, or Arg150Cys) decreased the binding affinity of U2AF2 for a consensus splice site RNA. Crystal structures at 1.4 Å resolutions showed that Arg149Trp or Arg150His disrupted hydrogen bonds between U2AF2 and the terminal nucleotides of the RNA site. Reanalysis of publicly available RNaseq data confirmed that U2AF2 depletion altered splicing of transcripts encoding RNA binding proteins (RBPs). These results confirmed that the impaired RNA interactions of Arg149Trp and Arg150His U2AF2 variants could contribute to dysregulating an RBP-governed neurodevelopmental program of alternative splicing.

PubMed: 39388459
DOI: 10.1021/acs.biochem.4c00344

Experimental method

X-RAY DIFFRACTION (1.4 Å)