4PCJ

Modifications to toxic CUG RNAs induce structural stability and rescue mis-splicing in Myotonic Dystrophy

Summary for 4PCJ

• Entry DOI: 10.2210/pdb4pcj/pdb
• Related: 4FNJ
• Descriptor: trCUG-3('5), MAGNESIUM ION (3 entities in total)
• Functional Keywords: pseudou, cug repeats, tetraloop receptor, rna
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 11375.22

Authors

Coonrod, L.A.,Reister, E.E.,Berglund, J.A. (deposition date: 2014-04-15, release date: 2014-10-29, Last modification date: 2023-09-27)

Primary citation

deLorimier, E.,Coonrod, L.A.,Copperman, J.,Taber, A.,Reister, E.E.,Sharma, K.,Todd, P.K.,Guenza, M.G.,Berglund, J.A.
Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model.
Nucleic Acids Res., 42:12768-12778, 2014

PubMed Abstract: CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein-RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.

PubMed: 25303993
DOI: 10.1093/nar/gku941

Experimental method

X-RAY DIFFRACTION (1.9 Å)