Abstract
RNA hairpins are the most commonly occurring secondary structural elements in RNAs and serve as nucleation sites for RNA folding, RNA-RNA, and RNA-protein interactions. RNA hairpins are frequently capped by tetraloops, and based on sequence similarity, three broad classes of RNA tetraloops have been defined: GNRA, UNCG, and CUYG. Other classes such as the UYUN tetraloop in histone mRNAs, the UGAA in 16S rRNA, the AUUA tetraloop from the MS2 bacteriophage, and the AGNN tetraloop that binds RNase III have also been characterized. The tetraloop structure is compact and is usually characterized by a paired interaction between the first and fourth nucleotides. The two unpaired nucleotides in the loop are usually involved in base-stacking or base-phosphate hydrogen bonding interactions. Several structures of RNA tetraloops, free and complexed to other RNAs or proteins, are now available and these studies have increased our understanding of the diverse mechanisms by which this motif is recognized. RNA tetraloops can mediate RNA-RNA contacts via the tetraloop-receptor motif, kissing hairpin loops, A-minor interactions, and pseudoknots. While these RNA-RNA interactions are fairly well understood, how RNA-binding proteins recognize RNA tetraloops and tetraloop-like motifs remains unclear. In this review, we summarize the structures of RNA tetraloop-protein complexes and the general themes that have emerged on sequence- and structure-specific recognition of RNA tetraloops. We highlight how proteins achieve molecular recognition of this nucleic acid motif, the structural adaptations observed in the tetraloop to accommodate the protein-binding partner, and the role of dynamics in recognition.