4BS2

NMR structure of human TDP-43 tandem RRMs in complex with UG-rich RNA

Summary for 4BS2

• Entry DOI: 10.2210/pdb4bs2/pdb
• NMR Information: BMRB: 19290
• Descriptor: TAR DNA-BINDING PROTEIN 43, 5'-R(*GP*UP*GP*UP*GP*AP*AP*UP*GP*AP*AP*UP)-3' (2 entities in total)
• Functional Keywords: transcription, hnrnp, cystic fibrosis, neurodegeneration, isotope-labelled rna, hammerhead ribozyme
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus : Q13148
• Total number of polymer chains: 2
• Total formula weight: 23873.09

Authors

Lukavsky, P.J.,Daujotyte, D.,Tollervey, J.R.,Ule, J.,Stuani, C.,Buratti, E.,Baralle, F.E.,Damberger, F.F.,Allain, F.H.T. (deposition date: 2013-06-06, release date: 2013-11-13, Last modification date: 2024-06-19)

Primary citation

Lukavsky, P.J.,Daujotyte, D.,Tollervey, J.R.,Ule, J.,Stuani, C.,Buratti, E.,Baralle, F.E.,Damberger, F.F.,Allain, F.H.T.
Molecular Basis of Ug-Rich RNA Recognition by the Human Splicing Factor Tdp-43
Nat.Struct.Mol.Biol., 20:1443-, 2013

PubMed Abstract: TDP-43 encodes an alternative-splicing regulator with tandem RNA-recognition motifs (RRMs). The protein regulates cystic fibrosis transmembrane regulator (CFTR) exon 9 splicing through binding to long UG-rich RNA sequences and is found in cytoplasmic inclusions of several neurodegenerative diseases. We solved the solution structure of the TDP-43 RRMs in complex with UG-rich RNA. Ten nucleotides are bound by both RRMs, and six are recognized sequence specifically. Among these, a central G interacts with both RRMs and stabilizes a new tandem RRM arrangement. Mutations that eliminate recognition of this key nucleotide or crucial inter-RRM interactions disrupt RNA binding and TDP-43-dependent splicing regulation. In contrast, point mutations that affect base-specific recognition in either RRM have weaker effects. Our findings reveal not only how TDP-43 recognizes UG repeats but also how RNA binding-dependent inter-RRM interactions are crucial for TDP-43 function.

PubMed: 24240615
DOI: 10.1038/NSMB.2698

Experimental method

SOLUTION NMR