RRMs

RNA recognition motif (RRM) is a common RNA-binding domain found in many eukaryotic RNA-binding proteins. RRMs are typically about 80–90 amino acids in length and can occur as single domains or in tandem repeats within a protein. They play key roles in post-transcriptional gene regulation by binding various RNA substrates, including mRNA transcripts.

Structurally, RRMs adopt a conserved β-sheet–driven fold, consisting of four antiparallel β-strands and two α-helices. The RNA-binding surface is formed mainly by the β-sheet. Within the domain, two highly conserved submotifs, known as RNP1 and RNP2, are located on different β-strands and serve as binding determinants. RNP1 is an octamer motif enriched for lysine or arginine residues and phenylalanines, while RNP2 is a hexamer motif rich in hydrophobic residues. The exact amino acids vary among RRMs, but the presence of these motifs is a hallmark of the domain.

RRMs bind predominantly single-stranded RNA, though their affinity and specificity are highly context-dependent. Tandem RRMs can create extended binding surfaces that recognize longer RNA motifs or allow cooperative binding, contributing to higher affinity and more precise regulatory outcomes. Functionally, RRMs participate in processes such as pre-mRNA splicing, mRNA localization, stability, and translational control. They are also involved in RNA processing and export within the nucleus and cytoplasm.

Distribution and significance: RRMs are widespread in eukaryotic RNA-binding proteins, including heterogeneous nuclear ribonucleoproteins (hnRNPs) and various splicing factors. Mutations or dysregulation of RRM-containing proteins can impact RNA metabolism and are associated with diverse diseases. RRMs exemplify a modular strategy by which cells regulate RNA function through versatile, sequence-adaptive binding domains.