title: Atomic resolution structure of CAG RNA repeats: structural insights and implications for the trinucleotide repeat expansion diseases.
abstract: CAG repeats occur predominantly in the coding regions of human genes, which suggests their functional importance. In some genes, these sequences can undergo pathogenic expansions leading to neurodegenerative polyglutamine (poly-Q) diseases. The mutant transcripts containing expanded CAG repeats possibly contribute to pathogenesis in addition to the well-known pathogenic effects of mutant proteins. We have analysed two crystal forms of RNA duplexes containing CAG repeats: (GGCAGCAGCC)(2). One of the structures has been determined at atomic resolution (0.95 Å) and the other at 1.9 Å. The duplexes include non-canonical A-A pairs that fit remarkably well within a regular A-helix. All the adenosines are in the anti-conformation and the only interaction within each A-A pair is a single C2-H2···N1 hydrogen bond. Both adenosines in each A-A pair are shifted towards the major groove, although to different extents; the A which is the H-bond donor stands out more (the 'thumbs-up' conformation). The main effect on the helix conformation is a local unwinding. The CAG repeats and the previously examined CUG structures share a similar pattern of electrostatic charge distribution in the minor groove, which could explain their affinity for the pathogenesis-related MBNL1 protein.
authors: Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
authors: Agnieszka
authors: A
authors: Kiliszek
authors: Ryszard
authors: R
authors: Kierzek
authors: Wlodzimierz J
authors: WJ
authors: Krzyzosiak
authors: Wojciech
authors: W
authors: Rypniewski
mesh_terms: D000225:Adenine / Q000737:chemistry; D020029:Base Pairing; D018360:Crystallography, X-Ray; D030342:Genetic Diseases, Inborn / Q000235:genetics; D006801:Humans; D007477:Ions / Q000737:chemistry; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012330:RNA, Double-Stranded / Q000737:chemistry*; D055672:Static Electricity; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats; D014867:Water / Q000737:chemistry
chemical_list: D007477:Ions; D012330:RNA, Double-Stranded; D014867:Water; D000225:Adenine