RNA structure generates natural cooperativity between single-stranded RNA binding proteins targeting 5′ and 3′UTRs

In post-transcriptional regulation, an mRNA molecule is bound by many proteins and/or miRNAs to modulate its function. To enable combinatorial gene regulation, these binding partners of an RNA must communicate with each other, exhibiting cooperativity. Even in the absence of direct physical interactions between the binding partners, such cooperativity can be mediated through RNA secondary structures, since they affect the accessibility of the binding sites. Here we propose a quantitative measure of this structure-mediated cooperativity that can be numerically calculated for an arbitrary RNA sequence. Focusing on an RNA with two binding sites, we derive a characteristic difference of free energy differences, i.e. ΔΔG, as a measure of the effect of the occupancy of one binding site on the binding strength of another. We apply this measure to a large number of human and Caenorhabditis elegans mRNAs, and find that structure-mediated cooperativity is a generic feature. Interestingly, this cooperativity not only affects binding sites in close proximity along the sequence but also configurations in which one binding site is located in the 5′UTR and the other is located in the 3′UTR of the mRNA. Furthermore, we find that this end-to-end cooperativity is determined by the UTR sequences while the sequences of the coding regions are irrelevant.