Abstract
Recently, the ability to interact with messenger RNA (mRNA) has been reported for a number of known RNA-binding proteins, but surprisingly also for different proteins without recognizable RNA binding domains including several transcription factors and metabolic enzymes. Moreover, direct binding to cognate mRNAs has been detected for multiple proteins, thus creating a strong impetus to search for functional significance and basic physico-chemical principles behind such interactions. Here, we derive interaction preferences between amino acids and RNA bases by analyzing binding interfaces in the known 3D structures of protein–RNA complexes. By applying this tool to human proteome, we reveal statistically significant matching between the composition of mRNA sequences and base-binding preferences of protein sequences they code for. For example, purine density profiles of mRNA sequences mirror guanine affinity profiles of cognate protein sequences with quantitative accuracy (median Pearson correlation coefficient R = −0.80 across the entire human proteome). Notably, statistically significant anti-matching is seen only in the case of adenine. Our results provide strong evidence for the stereo-chemical foundation of the genetic code and suggest that mRNAs and cognate proteins may in general be directly complementary to each other and associate, especially if unstructured.
Highlights
In the 50 years since the discovery of messenger RNA [1], the relationship between this key biopolymer and proteins has been studied predominantly in the context of transmission of genetic information and protein synthesis
We have recently shown that pyrimidine (PYR) density profiles of messenger RNA (mRNA) sequences tend to closely mirror sequence profiles of the respective cognate proteins capturing their amino-acid affinity for pyridines, chemicals closely related to PYR [15]
High levels of matching between base-binding-preference profiles of proteins and PYR- or PUR-density profiles of cognate mRNA-coding sequences, defined primarily by amino acid preferences to co-localize with G and C bases at RNA/protein interfaces, allow one to speculate that direct complementary binding interactions may be a key element underlying the whole mRNA/protein relationship when it comes to both its evolutionary development as well as present day biology (Figure 5B)
Summary
In the 50 years since the discovery of messenger RNA (mRNA) [1], the relationship between this key biopolymer and proteins has been studied predominantly in the context of transmission of genetic information and protein synthesis. Evidence of direct non-covalent binding between mRNAs and a number of functionally diverse proteins has been provided, including surprisingly various metabolic enzymes, transcription factors and scaffolding proteins with hitherto uncharacterized RNA-binding domains [2,3,4,5]. Several proteins have been found over the years to directly bind their own cognate mRNAs, including among others thymidylate synthase, dihydrofolate reductase and p53 [2,9,10,11,12,13,14], with binding sites in both translated and untranslated mRNA regions. The rapid growth of the number of experimentally verified mRNA-binding proteins, both cognate and non-cognate, has created a strong incentive to search for the functional significance of such interactions and, even more fundamentally, the basic physico-chemical rules that guide them
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