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Towards Deciphering the Principles Underlying an Mrna Recognition Code Alexander Serganov and Dinshaw J Patel

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Towards Deciphering the Principles Underlying an Mrna Recognition Code Alexander Serganov and Dinshaw J Patel Available online at www.sciencedirect.com Towards deciphering the principles underlying an mRNA recognition code Alexander Serganov and Dinshaw J Patel Messenger RNAs interact with a number of different molecules potential and opportunities for manipulation of gene that determine the fate of each transcript and contribute to the expression at the post-transcriptional level, many struc- overall pattern of gene expression. These interactions are tural biology groups have focused their ongoing research governed by specific mRNA signals, which in principle could efforts toward determination of structures that would represent a special mRNA recognition ‘code’. Both, small uncover the complex network of relationships between molecules and proteins demonstrate a diversity of mRNA mRNA and its partners, thereby contributing toward a binding modes often dependent on the structural context of the comprehensive understanding of the principles under- regions surrounding specific target sequences. In this review, lying a ‘mRNA recognition code’. we have highlighted recent structural studies that illustrate the diversity of recognition principles used by mRNA binders for Although the past decade of intensive research has pro- timely and specific targeting and processing of the message. vided us with molecular details of many interesting intermolecular interactions involving mRNA, the past Addresses two years have been especially informative, with over Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 30 structures reported of complexes containing mRNA. New York, NY 10021, USA This review analyzes recently published structural data (spanning 2006–2007) on specific mRNA recognition Corresponding author: Serganov, Alexander ([email protected]) and Patel, Dinshaw J ([email protected]) events and complements excellent earlier reviews on protein–RNA [2–5] and metabolite–mRNA [6–8] recog- nition. Current Opinion in Structural Biology 2008, 18:120–129 This review comes from a themed issue on The distinct modes of mRNA recognition Protein–nucleic acid interactions For the purpose of this review, we have considered Edited by Wei Yang and Greg van Duyne protein data bank (PDB) entries that describe interactions of mRNA fragments or their mimetics with either small Available online 5th February 2008 molecules or proteins. We propose dividing all such 0959-440X/$ – see front matter complexes into three categories (Table 1): (1) struc- # 2008 Elsevier Ltd. All rights reserved. ture-specific recognition of folded RNAs (Figure 1a); DOI 10.1016/j.sbi.2007.12.006 (2) sequence-specific recognition of single-stranded RNAs (Figure 1b); (3) non-specific recognition of single-stranded RNAs (Figure 1c). Introduction Most complexes belong to the first group and are often Transcription does not simply transfer coding information characterized by unique structure-specific aspects of required for protein biosynthesis from DNA to mRNA. In mRNA recognition. About half of these complexes com- fact, transcription produces pre-mRNA and mRNA mol- prise long (70–150 nt) sensing domains of riboswitch ecules, which carry multiple signals required for proces- mRNAs bound to their ligands (Figure 1a, left panel). sing, modification, transport, translation, and degradation The other half contains protein domain(s) bound to of the message. These signals are recognized by mRNA- shorter RNAs, which typically adopt stem–loop scaffolds binding molecules in both sequence-specific and struc- (Figure 1a, middle and right panels). The second group ture-dependent manner and help define the spatial and features protein domain(s) that interact with sequence- temporal constraints for translation of mRNA species. specificity to short single-stranded mRNA fragments The mRNA recognition signatures, therefore, could be (Figure 1b). The third group, not discussed in the current considered a special ‘code’, contributing, along with other review, mostly includes proteins and protein assemblies layers of gene expression control, to the final pattern of capable of binding various RNA species in a non- gene expression. This code, however, is unlikely to be sequence specific manner (Figure 1c). universal owing to dramatic differences in transcription and mRNA processing among evolutionary distant Interactions of small molecules with higher groups, as well as occurrence of species-specific order mRNA structures mRNA-recognition systems necessary for adaptation to Ribosensors are mRNA sequences that control gene particular environmental cues [1]. Owing to the immense expression in response to various stimuli, such as metab- Current Opinion in Structural Biology 2008, 18:120–129 www.sciencedirect.com mRNA recognition principles Serganov and Patel 121 Table 1 Pre-mRNA and mRNA recognition by small molecules and proteinsa Protein/metabolite Type of RNA Function Technique/ References, resolutionb protein data bank codes Specific binding of folded RNAs Metabolite/cation recognition Thiamine pyrophosphate (TPP) Bacterial riboswitch Regulation of transcription 2.05–3.5 A˚ 2GDI [12]; and analogs and translation 2HOJ [11] TPP Plant riboswitch Regulation of splicing and 2.9 A˚ 2CKY [13] processing S-adenosyl-methionine (SAM) SAM type I riboswitch Regulation of transcription 2.9 A˚ 2GIS [14] Glucosoamin-6-phopshate glmS ribozyme Gene expression control 2.1–2.9 A˚ 2GCV [16]; and analogs 2NZ4 [15] Mg2+ M-box riboswitch Regulation of transcription 2.6 A˚ 2QBZ [18] Protein recognition Ribosomal protein L1 K-turn-like element Repression of translation 2.1, 2.6 A˚ 2HW8, 1ZHO [21] Ribosomal protein S15, ribosome Pseudoknot and stem–loop Repression of translation Cryo-EM 2VAZ [29] IRP-1 Stem–loop, iron-responsive Repression of translation and 2.8 A˚ 2IPY [30] element RNA degradation RsmE Stem–loop, consensus Repression of translation NMR 2JPP [34] A U /UCANGGANG /A KH1/2 domains of NOVA-1 Aptamer, stem–loop, Alternative splicing 1.94 A˚ 2ANR consensus (YCAN)2 [Unpublished] Human RBMY Aptamer, stem–loop, Pre-mRNA processing? NMR 2FY1 [35] A consensus C /UCAA SAM domain of Vts1 Stem–loop, Smaug recognition Regulation of translation and NMR, NMR, 2.8 A˚ 2B6G [43]; element mRNA stability? 2ESE [44]; 2F8K [42] Elongation factor SELB Stem–loop, SECIS element Incorporation of selenocysteine 2.31 A˚ 2UWM [39] Exonuclease ERI1 Stem–loop Histone mRNA degradation 3.0 A˚ 1ZBH [Unpublished] Specific ssRNA binding Fox-1 U-GCAUG-U Alternative splicing NMR 2ERR [45] A A A RRM domain of SRp20 CAUC, consensus /UC /U /UC mRNA splicing and transport NMR 2I2Y [46 ] 65 ˚ Splicing factor U2AF U7 mRNA splicing 2.5 A 2G4B [47 ] Hrp1 Polyadenylation enhancement 30-end modification NMR 2CJK [51] element G-(UA)4 ˚ La autoantigen UGCUGU-UUUOH RNA stability, mRNA binding 1.85 A 1ZH5 [50 ] RNase KID AUACA Endonuclease NMR model 2C06 [52] KH1 domain of poly(C)- C-rich telomer-like sequence Diverse functions, mRNA 2.6 A˚ 2PY9 [53] binding protein 2 stability Non-specific ssRNA binding Archaeal exosome mRNA mimetic RNA degradation 2.3 A˚ 2JEA [54] Rho termination factor Pyrimidine-rich RNA Transcription termination 3.5 A˚ 2HT1[55] RNase II Poly(A) RNA RNA degradation 2.7 A˚ 2IX1 [56] Exon junction complex mRNA mimetic Splicing 2.3 A˚ , 2HYI [57]; 3.2 A˚ , 2J0Q, 2J0S [58] 2.2 A˚ Vasa mRNA mimetic mRNA unwinding 2.2 A˚ 2DB3 [59] RNase III dsRNA Cleavage of dsRNA 2.05 A˚ 2EZ6 [60] a Ribosomes and RNA polymerases bound to mRNA fragments as well as complexes between proteins and viral RNAs are not considered in the review. b Resolution is indicated for X-ray crystallographic structures. olites (riboswitches), cations (metallosensors), and thermosensor [17] and a Mg2+ ribosensor [18]. Here, temperature (thermosensors). Recently, the seminal we focus on the recent structure of the Mg2+ ribosensor, structure determination of purine-sensing riboswitches since it was not discussed in an earlier review [6]. [9,10] has been rapidly followed by structures of five more ribosensors: bacterial [11,12] and plant [13] Mg2+, the most abundant divalent cation, is crucially thiamine pyrophosphate (TPP) riboswitches, a S-adeno- required for both structure and function of many RNAs, sylmethionine type I (SAM-I) riboswitch [14], a glucosa- including mRNAs. Therefore, it was surprising to mine-6-phosphate-sensing glmS ribozyme [15,16], a find that Mg2+ homeostasis in Salmonella enterica and in www.sciencedirect.com Current Opinion in Structural Biology 2008, 18:120–129 122 Protein–nucleic acid interactions Figure 1 phosphate oxygens. Since Mg1 uses four inner sphere (one nucleobase and three sugar–phosphate backbone) contacts with RNA (Figure 2e), a feature rarely observed in previous studies, this cation might provide a key contribution to the docking of the J2-1/P2 region with the L4 and L5 loops. These long-distance interactions facilitate the formation of tertiary base contacts and base stacking, which in turn sequester anti-terminator nucleo- tides and, along with Watson-Crick base pairing, contrib- ute to the stabilization of helix P1, leading to the formation of the terminator hairpin and the repression of gene expression (Figure 2b). By contrast, in purine, TPP and SAM-I riboswitches, formation of the P1 helix is dependent on stabilization of the adjacent junction by bound ligand (Figure 2a) [9,11–14]. Recognition of three-dimensional mRNA structures by proteins Proposed division of various mRNA-recognition modes based on the Similar to riboswitches, some bacterial proteins inhibit structure- and sequence-specificity. Sequence-specific and non- translation by interactions
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