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Recognition modes of RNA tetraloops and tetraloop‐like motifs by RNA‐binding proteins

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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. WIREs RNA 2014, 5:49–67. doi: 10.1002/wrna.1196 This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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Structure of the N‐terminal zinc knuckle of the Rous sarcoma virus (RSV) nucleocapsid (NC) protein bound to the UGCG tetraloop of stem‐loop SL‐C from the RSV Mψ packaging signal (PDB code 2IHX). (a) Summary schematic showing the hydrogen bonding and stacking interactions observed in the free UUCG tetraloop of the P1 helix from group I self‐splicing introns (PDB code 1HLX). (b) Summary schematic showing the hydrogen bonding and stacking interactions observed in the tetraloop when bound to the zinc knuckle (PDB code 2IHX). The sugar puckers and base configurations are color coded according to the key shown below the schematic. (c) The zinc knuckle is shown in purple and the RNA is in green. The side chains of Tyr22 and Tyr30 stack against the guanine nucleotide G218 of the tetraloop. The configurations of the ribose and bases correspond to the color code shown in the summary schematic (b). (d) Surface representation of the RSV zinc knuckle showing the hydrophobic cleft that accommodates G218.
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Structure of the SLBP RNA‐binding domain, ERI1, and histone mRNA hairpin ternary complex (PDB code 4HXH). (a) Summary schematic showing the hydrogen bonding and stacking interactions observed in the solution nuclear magnetic resonance (NMR) structure of the free UUUC tetraloops calculated by NMR. The structure of PDB code 1JWC is summarized on top and the structure of PDB code 1KKS is summarized below. (b) Summary schematic showing the hydrogen bonding and stacking interactions observed in the UUUC tetraloop when bound to both SLBP and ERI1. SLBP protein side chains that make specific contacts with the tetraloop are depicted in orange, and ERI1 side chains that make specific contacts with the tetraloop are depicted in black. (c) Superposition of the RNA backbone and side chains of the free UUUC tetraloop (shown in cyan) and the unfolded UUUC tetraloop when bound to both SLBP and ERI1 (shown in green). There is a loss of base stacking of all uridines in the protein‐bound complex and a reorientation of U13. (d) The sequence of the histone mRNA hairpin is shown. Nucleotides important for binding T171 phosphorylated SLBP are highlighted in red and orange. G7 and U14 are critical for interaction with phosphorylated SLBP and are shown in red. (e) Overall structure of the SLBP RNA‐binding domain (in orange), the histone mRNA stem‐loop (in green), and ERI1 (in purple) ternary complex (PDB code 4HXH). Helices in SLBP and the SAP domain are designated. (f) Close‐up of the histone mRNA tetraloop (in green) bound to the SLBP RNA‐binding domain (in orange) and ERI1 (in purple) in the ternary complex. Side chains in SLBP and the ERI1 SAP domain that contact the RNA are designated. (g) The structure of the ternary complex is color coded to show the variation in the Debye–Waller factor (or B‐factor) in the protein and RNA components of the complex. Very high B‐factors (shown in red) indicate regions of high mobility or where the electron density is more spread out. Regions with low B‐factors are shown in blue. Helix‐B or SLBP has the highest B‐factors in the ternary complex. (h) Crystal contacts observed in the structure of the ternary complex are shown. The crystal shows extensive packing interactions between the nuclease domain of ERI1 from a binary ERI1/RNA complex (in yellow) that lacks SLBP, and the nuclease domain of a neighboring ERI1 molecule (in purple) from the ternary complex. The SLBP RNA‐binding domain is shown in orange. Helix‐B of SLBP contacts the SAP domain of ERI1 from a neighboring binary complex. The RNA is shown in green (ternary complex) or cyan (binary complex).
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Structure of restrictocin bound to the GAGA SRL tetraloop. (a) Summary schematic showing the hydrogen bonding and stacking interactions observed in the free GAGA tetraloop (PDB code 430D). The sugar puckers and base configurations are color coded according to the key shown in Figure 1(b). (b) Summary schematic showing the hydrogen bonding and stacking interactions observed in the GAGA tetraloop when bound to restrictocin (PDB code 1JBR). Protein side chains that make specific contacts with the tetraloop are depicted. (c) Superposition of the RNA backbone and side chains of the free GAGA tetraloop (shown in cyan) and the unfolded GAGA tetraloop when bound to the toxin (shown in green). (d) Overall structure of restrictocin bound to the RNA hairpin. The protein is shown in purple cartoon and the RNA is shown in green. The position of the bulged‐G motif relative to the tetraloop is highlighted. (e) Close‐up of the protein–RNA‐binding interface. The protein side chains are in gray and the RNA ribose and bases are color coded as shown in (b).
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Structure of the MS2 coat protein bound to the AUUA tetraloop from its RNA genome. (a) Summary schematic showing the hydrogen bonding and stacking interactions observed in the AUUA tetraloop in the absence of the MS2 coat protein (PDB code 1D0T). (b) Summary schematic showing the hydrogen bonding and stacking interactions observed in the AUUA tetraloop when bound to the MS2 coat protein (PDB code 1ZDH). The sugar puckers and base configurations are color coded according to the key shown in Figure 1(c). Specific interaction of the bases with protein side chains is depicted. (c) Overall structure of the MS2 dimer bound to the RNA hairpin. The protein is shown in purple cartoon and the RNA is shown in green. (d) Surface representation of the MS2 coat protein showing hydrophobic clefts that accommodate the 4A and 10A adenosines. The RNA is shown in green and the colors of the ribose sugar puckers correlate with the summary schematic in (b). The C3′‐endo configuration is shown in blue and the C2′‐endo configuration is shown in pink. (e) Close‐up of the MS2–RNA‐binding interface. The protein side chains are in gray and the RNA ribose and bases are color coded according to the key shown in Figure 1(b).
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Structures of λ and P22 bacteriophage N‐peptides bound to the GNRA‐like boxB RNA tetraloops. (a, b) The summary schematic showing the hydrogen bonding and stacking interactions observed in the free GAAA tetraloop (PDB code 1ZIF) and free GCAUA GAAA‐like tetraloop (PDB code 1LC6), respectively. (c–e) Structure of the λ N‐peptide‐boxB RNA complex (PDB coordinates are undeposited and were obtained from Dr Legault, University of Montreal, Canada). The peptide is shown in purple and the RNA is in green. In (c), the summary schematic showing the hydrogen bonding and stacking interactions observed in the tetraloop when bound to the peptide is shown. The specific interaction of the bases with protein side chains is highlighted. In (d), the shape‐specific recognition of the bent helix of the λ N‐peptide with the major groove of the RNA is shown. The RNA surface is shown in green. The small purple surface on the RNA shows the position of G11 in the tetraloop. The color codes are similar to that of the schematic shown in (c). In (e), the specific interactions between the protein side chains and the RNA bases are depicted in cartoon format. (f–h) Structure of the P22‐ARM peptide‐boxB RNA complex (PDB code 1A4T). The peptide is shown in purple and the RNA is in green. The N‐peptide forms a bent α‐helix with extensive ionic interactions with the major groove face of the GNRA‐like hairpin. The summary schematic is in (f), the surface representation in (g), and the side chain to base contacts depicted in cartoon format in (h).
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Structure of the Rnt1p dsRBD bound to cognate (PDB code 1T4L) and noncognate (PDB code 2LBS) (A/U)GNN tetraloops. (a) Summary schematic showing the hydrogen bonding and stacking interactions observed in the free AGAA tetraloop (PDB code 1K4A) is shown. In (b), the summary schematic for hydrogen bonding and stacking interactions observed in the free AAGU tetraloop (PDB code 2HNS) is shown. (c) Summary schematic showing the hydrogen bonding and stacking interactions observed in the complex formed by the cognate AGAA tetraloop bound to the Rnt1p dsRBD (PDB code 1T4L). The sugar puckers and base configurations are color coded according to the key shown in Figure 1(c). Protein side chains that contact the base and the sugars are depicted. (d) Overall structure of the Rnt1p dsRBD bound to the AGAA tetraloop. The protein is shown in purple and the RNA surface is shown in green. The protein contacts the successive minor, major, and minor groove via α‐helix1, the β3‐α2 loop, and the β1‐β2 loop, respectively. (e) A close‐up of the interaction of α‐helix1 with the RNA tetraloop is shown. (f) Summary schematic showing the hydrogen bonding and stacking interactions observed in the noncognate AAGU tetraloop bound to the Rnt1p dsRBD complex (PDB code 2LBS). Protein side chains that contact the base and the sugars are depicted. In panels (g) and (h), the specific contacts between the protein side chains of α‐helix1 and the RNA bases of the AGAA and AAGU tetraloops are compared. The AGAA tetraloop is in panel (g) and the AAGU tetraloop is in panel (h).
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RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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