‘Z-DNA like’ fragments in RNA: a recurring structural motif with implications for folding, RNA/protein recognition and immune response

Abstract

Since the work of Alexander Rich, who solved the first Z-DNA crystal structure, we have known that d(CpG) steps can adopt a particular structure that leads to forming left-handed helices. However, it is still largely unrecognized that other sequences can adopt ‘left-handed’ conformations in DNA and RNA, in double as well as single stranded contexts. These ‘Z-like’ steps involve the coexistence of several rare structural features: a C2’-endo puckering, a syn nucleotide and a lone pair–π stacking between a ribose O4’ atom and a nucleobase. This particular arrangement induces a conformational stress in the RNA backbone, which limits the occurrence of Z-like steps to ≈0.1% of all dinucleotide steps in the PDB. Here, we report over 600 instances of Z-like steps, which are located within r(UNCG) tetraloops but also in small and large RNAs including riboswitches, ribozymes and ribosomes. Given their complexity, Z-like steps are probably associated with slow folding kinetics and once formed could lock a fold through the formation of unique long-range contacts. Proteins involved in immunologic response also specifically recognize/induce these peculiar folds. Thus, characterizing the conformational features of these motifs could be a key to understanding the immune response at a structural level.

Revisiting GNRA and UNCG folds: U-turns versus Z-turns in RNA hairpin loops

“…Loop dimorphism was also observed in larger motifs containing GNRA sequences, such as the phylogenetically conserved 7-nt uGAAAgg loop that caps helix 35a in domain II of large ribosomal subunits (Hsiao et al 2006;Nasalean et al 2009;D'Ascenzo et al 2016). In every X-ray and cryo-EM structure of a ribosome available to date (including mitochondrial ribosomes), this uGAAAgg-or uGACAgg in Homo sapiens mitochondrial ribosomes (PDB code: 4WT8; resolution: 3.4 Å) (Amunts et al 2015)-adopts a Z-turn (Fig.…”

Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2′-O methylations

“…In contrast, recognition of the bases is predominantly through sequence-nonspecific van der Waals and stacking interactions. The first dinucleotide (N1 and N2) adopts geometry similar to CpG dinucleotides found within Z-form RNA and UUCG tetraloops (39), and is tightly sandwiched between multiple protein residues ( Fig. S6 A and C).…”

“…When bound to IFIT1, N1 and N2 adopt a rare Z-RNA-like conformation that is dependent on their respective ribose conformations ( Fig. S6F) (39). Whereas N2 is in the favorable C3′-endo conformation, N1 adopts a C2′-endo conformation and places its 2′-OH in close proximity to the side chains of two highly conserved residues, R187 and Y157 ( Fig.…”

Short but Weak: The Z‐DNA Lone‐Pair⋅⋅⋅π Conundrum Challenges Standard Carbon Van der Waals Radii

“…a) Oxygen‐to‐guanine lp⋅⋅⋅π contact observed in a CpG Z‐step extracted from a Z‐DNA d (CpGpCpGpCpG) 2 duplex X‐ray structure . The CpG Z‐step is similar to those present in RNA tetraloops of the UNCG type . Key: ribose O4′ (yellow), cytosine carbon (wheat), guanine carbon (white), lp⋅⋅⋅π stacking contact (dashed line); see the Supporting Information, Figure S1 for broader Z‐DNA and UNCG contexts and Figure S2 for a DME⋅⋅⋅G and d ‐ribose⋅⋅⋅G system description.…”