The effect of RNA secondary structures on RNA-ligand binding and the modifier RNA mechanism: a quantitative model

Abstract

RNA-ligand binding often depends crucially on the local RNA secondary structure at the binding site. We develop here a model that quantitatively predicts the effect of RNA secondary structure on effective RNA-ligand binding activities based on equilibrium thermodynamics and the explicit computations of partition functions for the RNA structures. A statistical test for the impact of a particular structural feature on the binding affinities follows directly from this approach. The formalism is extended to describing the effects of hybridizing small "modifier RNAs" to a target RNA molecule outside its ligand binding site. We illustrate the applicability of our approach by quantitatively describing the interaction of the mRNA stabilizing protein HuR with AU-rich elements [Meisner et al. (2004), Chem. Biochem. in press]. We discuss our model and recent experimental findings demonstrating the effectivity of modifier RNAs in vitro in the context of the current research activities in the field of non-coding RNAs. We speculate that modifier RNAs might also exist in nature; if so, they present an additional regulatory layer for fine-tuning gene expression that could evolve rapidly, leaving no obvious traces in the genomic DNA sequences.

Predicting in vivo binding sites of RNA-binding proteins using mRNA secondary structure

“…Different approaches make different assumptions about the role of target site accessibility in RBP binding. The method we employed, as proposed by Hackermuller and coworkers (Hackermuller et al 2005), requires the whole site to be unpaired for the protein to bind. However, other methods, including the EF option of MEMERIS (Hiller et al 2006), and some methods used to predict target site accessibility for miRNAs (Robins et al 2005;Ellis et al 2007;Kertesz et al 2007;Long et al 2007;Geis et al 2008;Tafer et al 2008), allow target sites to be partially paired.…”

“…A role for accessibility in RBP binding has long been supported by in vitro selection (Levine et al 1993;Gao et al 1994) and measurements of in vitro binding affinity (Hackermuller et al 2005). More recently, motiffinding algorithms have been developed that use measures of RNA single-strandedness to more accurately recover some RBP motifs from in vitro selection binding data (Hiller et al 2006).…”

A Story of Growing Confusion: Genes and Their Regulation

“…One possible mechanism is the modification of (m)RNA structure as a consequence of the duplex formation between modifier and its target (m)RNA, which in turn can dramatically affect the binding affinity of the (m)RNA and a protein 25 . In summary, the available evidence points towards the existence of a large and very diverse pool of functional RNAs whose roles are predominantly regulatory.…”

RNAs everywhere: genome‐wide annotation of structured RNAs

“…Given the stable interactions, one might consider siRNA-like functions. Alternatively, it is conceivable that some of these genes act as "modifier RNAs" by influencing mRNA secondary structure (Hackermüller et al, 2005). The fact that these ncRNAs are conserved in sequence and structure may suggest that other co-factors, such as proteins which recognize specific structured binding motifs, are involved in their function.…”