Structural Biochemistry/The RNA recognition motif, a plastic RNA-binding platform to regulate post-transcriptional gene expression


The RNA recognition motif (RRM) is one of the most common protein domains in eukaryotes and is also found to a lesser extent in bacteria and viruses. Structural aspects that allow for high RNA binding affinity and specificity include two conserved RNP motifs in the center of the β-sheet, two external β-strands, loops, and the C and N-termini.


The RRM was first discovered in the late 1980s when it was observed that pre-mRNA and hnRNAs were always found in complex with proteins. Analysis of the mRNA PABP and hnRNP protein C showed a RNA-binding domain sequence of about 90 amino acids with eight conserved aromatic and positively charged residues. A second consensus sequence was subsequently discovered and these were called RNP 1 and RNP 2 and deemed necessary for binding RNA.

Structure of the RRM and RNA Protein ComplexEdit

The RRM folds into a αβ structure with β1α1 β2 β 3α2 β4 with one four stranded antiparallel β-sheet and two alpha helices that are positioned against the sheet. More than 30 RRM structures have been determined by X-ray crystallography and NMR and these structures show a surprising amount of variation in the arrangement of the alpha helices and beta sheets.

An archetype example of RRM binding structure is the DNA-protein complex formed by hnRNPA1, which can bind both DNA and RNA. In this DNA-RNPA1 complex, two deoxynucleotides, A209 and G210 stack on aromatic rings located on beta 1 strands and cause rearrangement of the nucleic acid on the beta sheet in which the 5’ end is on the first half of the sheet and the 3’ is on the second half. A third aromatic residue interacts with hydrophobically with carbohydrate rings of A209 and G210 and a positively charged side chain of the RNP forms a salt bridge with the phosphate between A209 and G210.

Affinity and SpecificityEdit

The RRM has high affinity and is highly specific. The two external beta strands play an important role in specificity. The beta sheet surface is not used in the same way for various RNA-protein complexes. In hnRNPA1 RRM1, each beta strand binds one nucleotide whereas in PABP RRM-1, nucleotides interact with beta 1 and 3 while the nucleotide in between interacts with the loop.

The N and C terminal regions enhance the RNA-binding affinity by increasing the protein-RNA interaction network. The base stacking on the aromatic residues mentioned earlier is sandwiched either by a protein side chain from the N-terminal region or the C-terminal region. The C terminus can also contribute to differentiating between DNA and RNA by interacting with the 2 ‘OH group of the sugar ring in a hydrogen bonding interaction.