Abstract
The structure of a 22-base-pair RNA helix with mismatched pyrimidine base pairs is reported. The helix contains two symmetry-related CUG sequences: a triplet-repeat motif implicated in myotonic dystrophy type 1. The CUG repeat contains a U-U mismatch sandwiched between Watson-Crick pairs. Additionally, the center of the helix contains a dimerized UUCG motif with tandem pyrimidine (U-C/C-U) mismatches flanked by U-G wobble pairs. This region of the structure is significantly different from previously observed structures that share the same sequence and neighboring base pairs. The tandem pyrimidine mismatches are unusual and display sheared, cross-strand stacking geometries that locally constrict the helical width, a type of stacking previously associated with purines in internal loops. Thus, pyrimidine-rich regions of RNA have a high degree of structural diversity.
Highlights
Cellular transcriptomes are large with myriad important biological functions
Myotonic dystrophy type 1 (DM1) is a heritable disease caused by the expansion of genomically encoded CUG repeats in the 30 untranslated region of the dystrophia myotonica protein kinase (DMPK) mRNA (Mirkin, 2007)
The electron density was well resolved for the entire RNA, which formed an intermolecular duplex in the crystal with the two strands related by twofold crystallographic symmetry; only one stand of the duplex is present in the crystallographic asymmetric unit [Fig. 1(c)]
Summary
Cellular transcriptomes are large with myriad important biological functions. only a few percent of the structural coordinates in the Worldwide Protein Data Bank correspond to RNA, and some of these are redundant. Crystal structures of RNAs containing CUG repeats have previously been determined (Coonrod et al, 2012; Kiliszek et al, 2009; Kumar et al, 2011; Mooers et al, 2005). In these structures, the CUG repeats are composed of C–G base pairs that sandwich U–U mismatches. It has previously been observed that during crystallization RNA hairpins containing UUCG tetraloops can dimerize into double helices in which the UUCG sequence forms non-Watson–Crick base pairs (Berger et al, 2019; Cruse et al, 1994; Holbrook et al, 1991). The dimerized UUCG sequence displays novel cross-strand stacking of pyrimidine pairs, with inter-strand hydrogen bonds between the uracil nucleobase on one strand and the uracil ribose 20 O atom of the opposite strand
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