Utilizing the GAAA tetraloop/receptor to facilitate crystal packing and determination of the structure of a CUG RNA helix.

ABSTRACT: Myotonic dystrophy type 1 (DM1) is a microsatellite expansion disorder caused by the aberrant expansion of CTG repeats in the 3'-untranslated region of the DMPK gene. When transcribed, the toxic RNA CUG repeats sequester RNA binding proteins, which leads to disease symptoms. The expanded CUG repeats can adopt a double-stranded structure, and targeting this helix is a therapeutic strategy for DM1. To improve our understanding of the 5'CUG/3'GUC motif and how it may interact with proteins and small molecules, we designed a short CUG helix attached to a GAAA tetraloop/receptor to facilitate crystal packing. Here we report the highest-resolution structure (1.95 Å) to date of a GAAA tetraloop/receptor and the CUG helix it was used to crystallize. Within the CUG helix, we identify two different forms of noncanonical U-U pairs and reconfirm that CUG repeats are essentially A-form. An analysis of all noncanonical U-U pairs in the context of CUG repeats revealed six different classes of conformations that the noncanonical U-U pairs are able to adopt.

SUBMITTER: Coonrod LA 

PROVIDER: S-EPMC3515634 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature