7vft
Crystal structure of rGGGC(CAG)5GUCC oligo
Structural highlights
Publication Abstract from PubMedPolyglutamine (polyQ) diseases are a type of inherited neurodegenerative disorders caused by cytosine-adenine-guanine (CAG) trinucleotide expansion within the coding region of the disease-associated genes. We previously demonstrated that a pathogenic interaction between expanded CAG RNA and the nucleolin (NCL) protein triggers the nucleolar stress and neuronal cell death in polyQ diseases. However, mechanisms behind the molecular interaction remain unknown. Here, we report a 1.45 A crystal structure of the r(CAG)5 oligo that comprises a full A'-form helical turn with widened grooves. Based on this structure, we simulated a model of r(CAG)5 RNA complexed with the RNA recognition motif 2 (RRM2) of NCL and identified NCL residues that are critical for its binding to CAG RNA. Combined with in vitro and in vivo site-directed mutagenesis studies, our model reveals that CAG RNA binds to NCL sites that are not important for other cellular functions like gene expression and rRNA synthesis regulation, indicating that toxic CAG RNA interferes with NCL functions by sequestering it. Accordingly, an NCL mutant that is aberrant in CAG RNA-binding could rescue RNA-induced cytotoxicity effectively. Taken together, our study provides new molecular insights into the pathogenic mechanism of polyQ diseases mediated by NCL-CAG RNA interaction. Molecular insights into the interaction of CAG trinucleotide RNA repeats with nucleolin and its implication in polyglutamine diseases.,An Y, Chen ZS, Chan HYE, Ngo JCK Nucleic Acids Res. 2022 Jul 22;50(13):7655-7668. doi: 10.1093/nar/gkac532. PMID:35776134[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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