Abstract
Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins.
Highlights
The interactions between RNA and protein molecules are essential for molecular processes both in cellular organisms, where they govern the assembly of the protein synthesizing macromolecular machineries, such as the ribosome and spliceosome[1], and in viruses, where they envelope the (RNA) genetic material by capsid formation[2], or enhance the efficiency of viral transcription [3]
In order to comparatively investigate the functional implications of conformational flexibility in these proteins, we have assembled a comprehensive dataset of RNA- and DNAbinding protein sequences and structures
Based on the distinct differences in the conservation profiles of de facto binding residues and those that mainly function as flexible linkers, it would seem likely that tools, such as DisCons[13]that investigate and quantify the conservation of both the amino acid sequence and the disordered nature of a protein may offer an additional layer of information that can complement and enhance the performance of RNA-binding site prediction software, such as RNABindR [47], NAPS[48] or RNAProB[49], even though some of these methods already take evolutionary information into account
Summary
The interactions between RNA and protein molecules are essential for molecular processes both in cellular organisms, where they govern the assembly of the protein synthesizing macromolecular machineries, such as the ribosome and spliceosome[1], and in viruses, where they envelope the (RNA) genetic material by capsid formation[2], or enhance the efficiency of viral transcription [3]. Due to their central role, protein-RNA complexes have been extensively studied and it soon became apparent that RNA-binding proteins are enriched in intrinsic structural disorder [4].
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