Recognition modes of <scp>RNA</scp> tetraloops and tetraloop‐like motifs by <scp>RNA</scp>‐binding proteins

<jats:p><jats:styled-content style="fixed-case">RNA</jats:styled-content> hairpins are the most commonly occurring secondary structural elements in <jats:styled-content style="fixed-case">RNAs</jats:styled-content> and serve as nucleation sites for <jats:styled-content style="fixed-case">RNA</jats:styled-content> folding, <jats:styled-content style="fixed-case">RNA–RNA</jats:styled-content>, and <jats:styled-content style="fixed-case">RNA</jats:styled-content>–protein interactions. <jats:styled-content style="fixed-case">RNA</jats:styled-content> hairpins are frequently capped by tetraloops, and based on sequence similarity, three broad classes of <jats:styled-content style="fixed-case">RNA</jats:styled-content> tetraloops have been defined: <jats:styled-content style="fixed-case">GNRA</jats:styled-content>, <jats:styled-content style="fixed-case">UNCG</jats:styled-content>, and <jats:styled-content style="fixed-case">CUYG</jats:styled-content>. Other classes such as the <jats:styled-content style="fixed-case">UYUN</jats:styled-content> tetraloop in histone <jats:styled-content style="fixed-case">mRNAs</jats:styled-content>, the <jats:styled-content style="fixed-case">UGAA</jats:styled-content> in <jats:styled-content style="fixed-case">16S rRNA</jats:styled-content>, the <jats:styled-content style="fixed-case">AUUA</jats:styled-content> tetraloop from the <jats:styled-content style="fixed-case">MS2</jats:styled-content> bacteriophage, and the <jats:styled-content style="fixed-case">AGNN</jats:styled-content> tetraloop that binds <jats:styled-content style="fixed-case">RNase III</jats:styled-content> 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 <jats:styled-content style="fixed-case">RNA</jats:styled-content> tetraloops, free and complexed to other <jats:styled-content style="fixed-case">RNAs</jats:styled-content> or proteins, are now available and these studies have increased our understanding of the diverse mechanisms by which this motif is recognized. <jats:styled-content style="fixed-case">RNA</jats:styled-content> tetraloops can mediate <jats:styled-content style="fixed-case">RNA–RNA</jats:styled-content> contacts via the tetraloop–receptor motif, kissing hairpin loops, A‐minor interactions, and pseudoknots. While these <jats:styled-content style="fixed-case">RNA–RNA</jats:styled-content> interactions are fairly well understood, how <jats:styled-content style="fixed-case">RNA</jats:styled-content>‐binding proteins recognize <jats:styled-content style="fixed-case">RNA</jats:styled-content> tetraloops and tetraloop‐like motifs remains unclear. In this review, we summarize the structures of <jats:styled-content style="fixed-case">RNA</jats:styled-content> tetraloop–protein complexes and the general themes that have emerged on sequence‐ and structure‐specific recognition of <jats:styled-content style="fixed-case">RNA</jats:styled-content> 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. <jats:italic>WIREs RNA</jats:italic> 2014, 5:49–67. doi: 10.1002/wrna.1196</jats:p><jats:p>This article is categorized under: <jats:list list-type="explicit-label"> <jats:list-item><jats:p>RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry</jats:p></jats:list-item> <jats:list-item><jats:p>RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition</jats:p></jats:list-item> <jats:list-item><jats:p>RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes</jats:p></jats:list-item> </jats:list></jats:p>