How RNA-Binding Proteins Interact with RNA: Molecules and Mechanisms
2020; Elsevier BV; Volume: 78; Issue: 1 Linguagem: Inglês
10.1016/j.molcel.2020.03.011
ISSN1097-4164
AutoresMeredith Corley, Margaret C. Burns, G Yeo,
Tópico(s)RNA and protein synthesis mechanisms
ResumoRNA-binding proteins (RBPs) comprise a large class of over 2,000 proteins that interact with transcripts in all manner of RNA-driven processes. The structures and mechanisms that RBPs use to bind and regulate RNA are incredibly diverse. In this review, we take a look at the components of protein-RNA interaction, from the molecular level to multi-component interaction. We first summarize what is known about protein-RNA molecular interactions based on analyses of solved structures. We additionally describe software currently available for predicting protein-RNA interaction and other resources useful for the study of RBPs. We then review the structure and function of seventeen known RNA-binding domains and analyze the hydrogen bonds adopted by protein-RNA structures on a domain-by-domain basis. We conclude with a summary of the higher-level mechanisms that regulate protein-RNA interactions. RNA-binding proteins (RBPs) comprise a large class of over 2,000 proteins that interact with transcripts in all manner of RNA-driven processes. The structures and mechanisms that RBPs use to bind and regulate RNA are incredibly diverse. In this review, we take a look at the components of protein-RNA interaction, from the molecular level to multi-component interaction. We first summarize what is known about protein-RNA molecular interactions based on analyses of solved structures. We additionally describe software currently available for predicting protein-RNA interaction and other resources useful for the study of RBPs. We then review the structure and function of seventeen known RNA-binding domains and analyze the hydrogen bonds adopted by protein-RNA structures on a domain-by-domain basis. We conclude with a summary of the higher-level mechanisms that regulate protein-RNA interactions. RNA-binding proteins (RBPs) potently and ubiquitously regulate transcripts throughout their life cycle (Lorković, 2012Lorković Z.J. RNA Binding Proteins. Landes Bioscience, 2012Crossref Google Scholar). RBP interactions with RNA range from single-protein-RNA element interaction to the assembly of multiple RBPs and RNA molecules such as the spliceosome. How RBPs selectively bind their targets is not always understood, although there are currently many techniques used to study these interactions. X-ray crystallography and nuclear magnetic resonance (NMR) experiments facilitate precise study of the amino acids and nucleotides that interact in protein-RNA complexes, and numerous such datasets have been generated for RBP domains in complex with RNA (Berman et al., 2000Berman H.M. Westbrook J. Feng Z. Gilliland G. Bhat T.N. Weissig H. Shindyalov I.N. Bourne P.E. The Protein Data Bank.Nucleic Acids Res. 2000; 28: 235-242Crossref PubMed Google Scholar). Analyses of these data have inferred the number and types of intermolecular interactions and preferred amino acids that characterize specific protein-RNA binding (Han and Nepal, 2007Han K. Nepal C. PRI-Modeler: extracting RNA structural elements from PDB files of protein-RNA complexes.FEBS Lett. 2007; 581: 1881-1890Crossref PubMed Scopus (0) Google Scholar, Pérez-Cano and Fernández-Recio, 2010Pérez-Cano L. Fernández-Recio J. Optimal protein-RNA area, OPRA: a propensity-based method to identify RNA-binding sites on proteins.Proteins. 2010; 78: 25-35Crossref PubMed Scopus (0) Google Scholar). Furthermore, numerous studies have built on protein-RNA structural data to develop increasingly accurate software that predicts which residues in proteins interact with RNA. We include a description of up-to-date software and data resources for the purpose of predicting and studying how RBPs interact with RNA. RNA-binding domains in protein are the functional units responsible for binding RNA. Multiple such domains often occur in a single RBP and these modular arrangements can coordinate and enhance binding to RNA (Cléry and Allain, 2012Cléry A. Allain F.H.T. From structure to function of RNA binding domains.in: Lorković Z.J. RNA Binding Proteins. Landes Bioscience, 2012: 137-158Google Scholar, Lunde et al., 2007Lunde B.M. Moore C. Varani G. RNA-binding proteins: modular design for efficient function.Nat. Rev. Mol. Cell Biol. 2007; 8: 479-490Crossref PubMed Scopus (627) Google Scholar). Additionally, RBPs tend to be enriched in intrinsically disordered regions, which themselves act as RNA-binding domains but limit the structural study of RBPs to ordered domains rather than full-length protein (Järvelin et al., 2016Järvelin A.I. Noerenberg M. Davis I. Castello A. The new (dis)order in RNA regulation.Cell Commun. Signal. 2016; 14: 9Crossref PubMed Google Scholar). Several ordered domains have been studied for decades, although it is important to note that RNA-binding domains are remarkably heterogeneous and can be difficult to classify (Gerstberger et al., 2014Gerstberger S. Hafner M. Tuschl T. A census of human RNA-binding proteins.Nat. Rev. Genet. 2014; 15: 829-845Crossref PubMed Scopus (510) Google Scholar). Additionally, many domains remain to be characterized, where hundreds of RBPs lack known RNA-binding domains (Castello et al., 2016Castello A. Fischer B. Frese C.K. Horos R. Alleaume A.M. Foehr S. Curk T. Krijgsveld J. Hentze M.W. Comprehensive identification of RNA-binding domains in human cells.Mol. Cell. 2016; 63: 696-710Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Here we overview the strategies that seventeen well-characterized RNA-binding domains use to achieve RNA binding. Furthermore, we present an analysis of the preferences in protein-RNA hydrogen bonds for eight of these domain types. RBP binding ultimately achieves a range of cellular goals (Gerstberger et al., 2014Gerstberger S. Hafner M. Tuschl T. A census of human RNA-binding proteins.Nat. Rev. Genet. 2014; 15: 829-845Crossref PubMed Scopus (510) Google Scholar, Glisovic et al., 2008Glisovic T. Bachorik J.L. Yong J. Dreyfuss G. RNA-binding proteins and post-transcriptional gene regulation.FEBS Lett. 2008; 582: 1977-1986Crossref PubMed Scopus (681) Google Scholar), but many mechanisms—and many chances for regulation—lie in between binding and biological consequence. These mechanisms we categorize into several layers: protein-RNA assembly, combined action of the ribonucleoprotein (RNP), and modifications and interactions that regulate the previous two (Lovci et al., 2016Lovci M.T. Bengtson M.H. Massirer K.B. Post-translational modifications and RNA-binding proteins.Adv. Exp. Med. Biol. 2016; 907: 297-317Crossref PubMed Scopus (10) Google Scholar, Lunde et al., 2007Lunde B.M. Moore C. Varani G. 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Structural insights into the molecular mechanism of the m(6)A writer complex.eLife. 2016; 5: e18434Crossref PubMed Google Scholar), all of which were discovered by intense and detailed biochemical work, including by insights from protein-RNA structures. These summaries intersect the areas of study that enable a mechanistic understanding of RBP regulation and we hope serve as a useful and timely resource. To understand RBP regulation of RNA targets, one must understand the biochemical underpinnings that facilitate exact and specific interaction with these sites. RBPs bind their RNA targets through the molecular interactions of chemical moieties between protein residues and RNA nucleotides. At this resolution the distinction between RNA and protein begins to blend, as the same intermolecular forces that shape protein and RNA tertiary structures also stitch the two molecules together. These interactions occur dynamically, with sometimes quite large rearrangements in RNA and protein (Hainzl et al., 2005Hainzl T. Huang S. Sauer-Eriksson A.E. Structural insights into SRP RNA: an induced fit mechanism for SRP assembly.RNA. 2005; 11: 1043-1050Crossref PubMed Scopus (27) Google Scholar, Leulliot and Varani, 2001Leulliot N. Varani G. Current topics in RNA-protein recognition: control of specificity and biological function through induced fit and conformational capture.Biochemistry. 2001; 40: 7947-7956Crossref PubMed Scopus (277) Google Scholar). In this section, we will provide a detailed description of the molecular interactions that occur in protein-RNA structures and overview trends determined by previous research. We will also catalog software that uses molecular-level interaction data to predict protein-RNA binding. Hydrogen bonds and Van der Waals (VdW) interactions have been extensively analyzed in protein-RNA interactions (Gupta and Gribskov, 2011Gupta A. Gribskov M. The role of RNA sequence and structure in RNA–protein interactions.J. Mol. Biol. 2011; 409: 574-587Crossref PubMed Scopus (36) Google Scholar, Han and Nepal, 2007Han K. Nepal C. PRI-Modeler: extracting RNA structural elements from PDB files of protein-RNA complexes.FEBS Lett. 2007; 581: 1881-1890Crossref PubMed Scopus (0) Google Scholar, Hoffman et al., 2004Hoffman M.M. Khrapov M.A. Cox J.C. Yao J. Tong L. Ellington A.D. AANT: the Amino Acid-Nucleotide Interaction Database.Nucleic Acids Res. 2004; 32: D174-D181Crossref PubMed Google Scholar, Pérez-Cano and Fernández-Recio, 2010Pérez-Cano L. Fernández-Recio J. Optimal protein-RNA area, OPRA: a propensity-based method to identify RNA-binding sites on proteins.Proteins. 2010; 78: 25-35Crossref PubMed Scopus (0) Google Scholar, Treger and Westhof, 2001Treger M. Westhof E. Statistical analysis of atomic contacts at RNA-protein interfaces.J. Mol. Recognit. 2001; 14: 199-214Crossref PubMed Scopus (0) Google Scholar). Hydrogen bonds form between an electronegative atom bound to a hydrogen atom, whose partial positive charge attracts an electronegative partner. Hydrogen bonds can be formed by both neutral and ionic groups, and can be coordinated by water molecules (Figure 1B). They generally form at distances of 2.4–3.0 Å, contributing 0.5–4.5 kcal/mol per bond (Auweter et al., 2006Auweter S.D. Oberstrass F.C. Allain F.H. Sequence-specific binding of single-stranded RNA: is there a code for recognition?.Nucleic Acids Res. 2006; 34: 4943-4959Crossref PubMed Scopus (206) Google Scholar). The weakest hydrogen bonds are considered to be VdW interactions, which are weak (0.5–1 kcal/mol) electrostatic interactions that occur above ∼3.0 Å. All the studies that analyze VdW interactions and hydrogen bonds in protein-RNA structures identify hydrogen bonds with HBPLUS (McDonald and Thornton, 1994McDonald I.K. Thornton J.M. Satisfying hydrogen bonding potential in proteins.J. Mol. Biol. 1994; 238: 777-793Crossref PubMed Scopus (1731) Google Scholar) and identify VdW interactions as the hydrogen bonds above a threshold donor-acceptor distance (Allers and Shamoo, 2001Allers J. Shamoo Y. Structure-based analysis of protein-RNA interactions using the program ENTANGLE.J. Mol. Biol. 2001; 311: 75-86Crossref PubMed Scopus (193) Google Scholar, Ellis et al., 2007Ellis J.J. Broom M. Jones S. Protein-RNA interactions: structural analysis and functional classes.Proteins. 2007; 66: 903-911Crossref PubMed Scopus (0) Google Scholar, Han and Nepal, 2007Han K. Nepal C. PRI-Modeler: extracting RNA structural elements from PDB files of protein-RNA complexes.FEBS Lett. 2007; 581: 1881-1890Crossref PubMed Scopus (0) Google Scholar, Hu et al., 2018Hu W. Qin L. Li M.L. Pu X.M. Guo Y.Z. A structural dissection of protein-RNA interactions based on different RNA base areas of interfaces.RSC Adv. 2018; 8: 10582-10592Crossref Google Scholar, Jones et al., 2001Jones S. Daley D.T.A. Luscombe N.M. Berman H.M. Thornton J.M. Protein-RNA interactions: a structural analysis.Nucleic Acids Res. 2001; 29: 943-954Crossref PubMed Google Scholar, Morozova et al., 2006Morozova N. Allers J. Myers J. Shamoo Y. Protein-RNA interactions: exploring binding patterns with a three-dimensional superposition analysis of high resolution structures.Bioinformatics. 2006; 22: 2746-2752Crossref PubMed Scopus (99) Google Scholar, Treger and Westhof, 2001Treger M. Westhof E. Statistical analysis of atomic contacts at RNA-protein interfaces.J. Mol. Recognit. 2001; 14: 199-214Crossref PubMed Scopus (0) Google Scholar). All RNA bases, the 2′ OH, and the phosphodiester backbone can form hydrogen bonds and VdW interactions with protein (Figures 1A–1C) (Teplova et al., 2011Teplova M. Malinina L. Darnell J.C. Song J. Lu M. Abagyan R. Musunuru K. Teplov A. Burley S.K. Darnell R.B. Patel D.J. Protein-RNA and protein-protein recognition by dual KH1/2 domains of the neuronal splicing factor Nova-1.Structure. 2011; 19: 930-944Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Multiple analyses of hydrogen-bond types in protein-RNA structures have found that hydrogen bonds with base, 2′ OH (sugar), and phosphate (RNA backbone) account for an average of 35.5%, 23.5%, and 41% of protein-RNA hydrogen bonds, respectively (Figure 2A) (Gupta and Gribskov, 2011Gupta A. Gribskov M. The role of RNA sequence and structure in RNA–protein interactions.J. Mol. Biol. 2011; 409: 574-587Crossref PubMed Scopus (36) Google Scholar, Han and Nepal, 2007Han K. Nepal C. PRI-Modeler: extracting RNA structural elements from PDB files of protein-RNA complexes.FEBS Lett. 2007; 581: 1881-1890Crossref PubMed Scopus (0) Google Scholar, Hoffman et al., 2004Hoffman M.M. Khrapov M.A. Cox J.C. Yao J. Tong L. Ellington A.D. AANT: the Amino Acid-Nucleotide Interaction Database.Nucleic Acids Res. 2004; 32: D174-D181Crossref PubMed Google Scholar, Treger and Westhof, 2001Treger M. Westhof E. Statistical analysis of atomic contacts at RNA-protein interfaces.J. Mol. Recognit. 2001; 14: 199-214Crossref PubMed Scopus (0) Google Scholar). Studies of VdW percentages with base, sugar, and phosphate are more variable (Figure 2B), perhaps reflecting inconsistent thresholds in categorizing VdW interactions.Figure 2Meta-analysis of Seven Studies Analyzing Hydrogen Bonds and Van der Waals Interactions in Protein-RNA StructuresShow full caption(A) Reports across studies of the percent of hydrogen bonds in protein-RNA structures that occur with the RNA backbone (phosphate), sugar (2′ OH), or base. The percent of hydrogen bonds that occur with the protein side chain (as opposed to the main chain). Averages are shown above each category.(B) Reports of the percent of VdW interactions in protein-RNA structures that occur with the RNA backbone (phosphate), sugar (2′ OH), or base. The percent of VdW interactions that occur with the protein side chain (as opposed to the main chain). Averages are shown above each category.(C) Reports across studies of the average ratio of VdW interactions to hydrogen bonds per protein-RNA structure.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Reports across studies of the percent of hydrogen bonds in protein-RNA structures that occur with the RNA backbone (phosphate), sugar (2′ OH), or base. The percent of hydrogen bonds that occur with the protein side chain (as opposed to the main chain). Averages are shown above each category. (B) Reports of the percent of VdW interactions in protein-RNA structures that occur with the RNA backbone (phosphate), sugar (2′ OH), or base. The percent of VdW interactions that occur with the protein side chain (as opposed to the main chain). Averages are shown above each category. (C) Reports across studies of the average ratio of VdW interactions to hydrogen bonds per protein-RNA structure. Proteins can interact with RNA using the main chain of any residue and the side chains of most residues. Studies have consistently found that the protein side chain, versus the main chain, is employed in 71.5% of hydrogen bonds and 76% of VdW interactions with RNA (Figures 2A and 2B). Polar amino acids Ser and Asn and positively charged amino acids Lys and Arg, which form strong ionic hydrogen bonds (salt bridges), predominate these interactions (Gupta and Gribskov, 2011Gupta A. Gribskov M. The role of RNA sequence and structure in RNA–protein interactions.J. Mol. Biol. 2011; 409: 574-587Crossref PubMed Scopus (36) Google Scholar, Han and Nepal, 2007Han K. Nepal C. PRI-Modeler: extracting RNA structural elements from PDB files of protein-RNA complexes.FEBS Lett. 2007; 581: 1881-1890Crossref PubMed Scopus (0) Google Scholar, Hoffman et al., 2004Hoffman M.M. Khrapov M.A. Cox J.C. Yao J. Tong L. Ellington A.D. AANT: the Amino Acid-Nucleotide Interaction Database.Nucleic Acids Res. 2004; 32: D174-D181Crossref PubMed Google Scholar, Pérez-Cano and Fernández-Recio, 2010Pérez-Cano L. Fernández-Recio J. Optimal protein-RNA area, OPRA: a propensity-based method to identify RNA-binding sites on proteins.Proteins. 2010; 78: 25-35Crossref PubMed Scopus (0) Google Scholar, Treger and Westhof, 2001Treger M. Westhof E. Statistical analysis of atomic contacts at RNA-protein interfaces.J. Mol. Recognit. 2001; 14: 199-214Crossref PubMed Scopus (0) Google Scholar). VdW interactions generally share the same preferences for amino acids that are observed for hydrogen bonds (Ellis et al., 2007Ellis J.J. Broom M. Jones S. Protein-RNA interactions: structural analysis and functional classes.Proteins. 2007; 66: 903-911Crossref PubMed Scopus (0) Google Scholar, Han and Nepal, 2007Han K. Nepal C. PRI-Modeler: extracting RNA structural elements from PDB files of protein-RNA complexes.FEBS Lett. 2007; 581: 1881-1890Crossref PubMed Scopus (0) Google Scholar, Jones et al., 2001Jones S. Daley D.T.A. Luscombe N.M. Berman H.M. Thornton J.M. Protein-RNA interactions: a structural analysis.Nucleic Acids Res. 2001; 29: 943-954Crossref PubMed Google Scholar, Treger and Westhof, 2001Treger M. Westhof E. Statistical analysis of atomic contacts at RNA-protein interfaces.J. Mol. Recognit. 2001; 14: 199-214Crossref PubMed Scopus (0) Google Scholar). In the overall set of interactions that occur at a protein-RNA interface, VdW interactions are thought to predominate, although estimates of the ratio of VdW-to-hydrogen-bond interactions per protein-RNA complex vary quite a bit (Figure 2C). Hydrophobic interactions occur at distances of 3.8 –5.0 Å (Morozova et al., 2006Morozova N. Allers J. Myers J. Shamoo Y. Protein-RNA interactions: exploring binding patterns with a three-dimensional superposition analysis of high resolution structures.Bioinformatics. 2006; 22: 2746-2752Crossref PubMed Scopus (99) Google Scholar, Onofrio et al., 2014Onofrio A. Parisi G. Punzi G. Todisco S. Di Noia M.A. Bossis F. Turi A. De Grassi A. Pierri C.L. Distance-dependent hydrophobic-hydrophobic contacts in protein folding simulations.Phys. Chem. Chem. Phys. 2014; 16: 18907-18917Crossref PubMed Google Scholar) and contribute 1–2 kcal/mol per interaction (Dill et al., 2008Dill K.A. Ozkan S.B. Shell M.S. Weikl T.R. The protein folding problem.Annu. Rev. Biophys. 2008; 37: 289-316Crossref PubMed Scopus (588) Google Scholar). Hydrophobic interactions between RNA bases and hydrophobic side chains can be important stabilizing factors at protein-RNA interfaces by sequestering hydrophobic residues and bases from solvent to form a “hydrophobic core” (Akopian et al., 2013Akopian D. Shen K. Zhang X. Shan S.O. Signal recognition particle: an essential protein-targeting machine.Annu. Rev. Biochem. 2013; 82: 693-721Crossref PubMed Scopus (177) Google Scholar, Allain et al., 1997Allain F.H. Howe P.W. Neuhaus D. Varani G. Structural basis of the RNA-binding specificity of human U1A protein.EMBO J. 1997; 16: 5764-5772Crossref PubMed Scopus (141) Google Scholar, Yang et al., 2002Yang Y. Declerck N. Manival X. Aymerich S. Kochoyan M. Solution structure of the LicT-RNA antitermination complex: CAT clamping RAT.EMBO J. 2002; 21: 1987-1997Crossref PubMed Scopus (46) Google Scholar, Yu et al., 2014Yu Q. Ye W. Jiang C. Luo R. Chen H.F. Specific recognition mechanism between RNA and the KH3 domain of Nova-2 protein.J. Phys. Chem. B. 2014; 118: 12426-12434Crossref PubMed Scopus (3) Google Scholar). For example, the SRP54 “M”-binding domain forms a methionine-rich hydrophobic surface with SRP RNA (Akopian et al., 2013Akopian D. Shen K. Zhang X. Shan S.O. Signal recognition particle: an essential protein-targeting machine.Annu. Rev. Biochem. 2013; 82: 693-721Crossref PubMed Scopus (177) Google Scholar). Hydrophobic interactions have been surveyed more sparsely in protein-RNA structures, but may account for up to 50% of the interactions at the protein-RNA interface, depending on the RBP (Hu et al., 2018Hu W. Qin L. Li M.L. Pu X.M. Guo Y.Z. A structural dissection of protein-RNA interactions based on different RNA base areas of interfaces.RSC Adv. 2018; 8: 10582-10592Crossref Google Scholar). π interactions can form between any nitrogenous base ring and a π-containing amino acid, which include the aromatic residues Trp, His, Phe, and Tyr as well as the charged residues Arg, Glu, and Asp (Wilson et al., 2016Wilson K.A. Holland D.J. Wetmore S.D. Topology of RNA-protein nucleobase-amino acid π-π interactions and comparison to analogous DNA-protein π-π contacts.RNA. 2016; 22: 696-708Crossref PubMed Scopus (4) Google Scholar). These interactions are relatively strong at ∼2–6 kcal/mol per interaction (Brylinski, 2018Brylinski M. Aromatic interactions at the ligand-protein interface: implications for the development of docking scoring functions.Chem. Biol. Drug Des. 2018; 91: 380-390Crossref PubMed Scopus (0) Google Scholar, Wilson et al., 2016Wilson K.A. Holland D.J. Wetmore S.D. Topology of RNA-protein nucleobase-amino acid π-π interactions and comparison to analogous DNA-protein π-π contacts.RNA. 2016; 22: 696-708Crossref PubMed Scopus (4) Google Scholar), and often prefer to be stacked (referred to as π stacking), occurring most frequently with an inter-atom distance of 2.7–4.3 Å (Auweter et al., 2006Auweter S.D. Oberstrass F.C. Allain F.H. Sequence-specific binding of single-stranded RNA: is there a code for recognition?.Nucleic Acids Res. 2006; 34: 4943-4959Crossref PubMed Scopus (206) Google Scholar, Brylinski, 2018Brylinski M. Aromatic interactions at the ligand-protein interface: implications for the development of docking scoring functions.Chem. Biol. Drug Des. 2018; 91: 380-390Crossref PubMed Scopus (0) Google Scholar, Morozova et al., 2006Morozova N. Allers J. Myers J. Shamoo Y. Protein-RNA interactions: exploring binding patterns with a three-dimensional superposition analysis of high resolution structures.Bioinformatics. 2006; 22: 2746-2752Crossref PubMed Scopus (99) Google Scholar, Wilson et al., 2016Wilson K.A. Holland D.J. Wetmore S.D. Topology of RNA-protein nucleobase-amino acid π-π interactions and comparison to analogous DNA-protein π-π contacts.RNA. 2016; 22: 696-708Crossref PubMed Scopus (4) Google Scholar). Analyses of π interactions occurring in protein-RNA crystal structures find multiple such interactions on average per structure (Hu et al., 2018Hu W. Qin L. Li M.L. Pu X.M. Guo Y.Z. A structural dissection of protein-RNA interactions based on different RNA base areas of interfaces.RSC Adv. 2018; 8: 10582-10592Crossref Google Scholar, Wilson et al., 2016Wilson K.A. Holland D.J. Wetmore S.D. Topology of RNA-protein nucleobase-amino acid π-π interactions and comparison to analogous DNA-protein π-π contacts.RNA. 2016; 22: 696-708Crossref PubMed Scopus (4) Google Scholar). These interactions can contribute considerable stability to protein-RNA binding, where some π interactions are demonstrably crucial to binding function (Auweter et al., 2006Auweter S.D. Oberstrass F.C. Allain F.H. Sequence-specific binding of single-stranded RNA: is there a code for recognition?.Nucleic Acids Res. 2006; 34: 4943-4959Crossref PubMed Scopus (206) Google Scholar, Liao et al., 2018Liao S. Sun H. Xu C. YTH domain: a family of N6-methyladenosine (m6A) readers.Genomics Proteomics Bioinformatics. 2018; 16: 99-107Crossref PubMed Scopus (0) Google Scholar, Oubridge et al., 1994Oubridge C. Ito N. Evans P.R. Teo C.H. Nagai K. Crystal structure at 1.92 Å resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin.Nature. 1994; 372: 432-438Crossref PubMed Scopus (0) Google Scholar). Such is the case with the extensive stacking interactions cementing human U1A spliceosomal protein with an RNA polyadenylation inhibition element, including two consecutive bases sandwiched between Phe and Asp residues (Figure 1D) (Oubridge et al., 1994Oubridge C. Ito N. Evans P.R. Teo C.H. Nagai K. Crystal structure at 1.92 Å resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin.Nature. 1994; 372: 432-438Crossref PubMed Scopus (0) Google Scholar). Stacking interactions also occur between bases and hydrophobic residues, and these may be mixed with π-π stacking interactions. For example, a single cytosine in a bulge in bacterial 4.5S SRP RNA stacks with both Phe and Leu in FtsY (Bifsha et al., 2007Bifsha P. Landry K. Ashmarina L. Durand S. Seyrantepe V. Trudel S. Quiniou C. Chemtob S. Xu Y. Gravel R.A. et al.Altered gene expression in cells from patients with lysosomal storage disorders suggests impairment of the ubiquitin pathway.Cell Death Differ. 2007; 14: 511-523Crossref PubMed Scopus (0) Google Scholar). More exotic π-stacking configurations include bases that stack on the protein main chain between residues (Auweter et al., 2006Auweter S.D. Oberstrass F.C. Allain F.H. Sequence-specific binding of single-stranded RNA: is there a code for recognition?.Nucleic Acids Res. 2006; 34: 4943-4959Crossref PubMed Scopus (206) Google Scholar) and perpendicular “T stacks” between protein side chains and bases. Stacking interactions with RNA are overall quite crucial and varied, possibly occurring at higher rates than in protein-DNA interactions (Wilson et al., 2016Wilson K.A. Holland D.J. Wetmore S.D. Topology of RNA-protein nucleobase-amino acid π-π interactions and comparison to analogous DNA-protein π-π contacts.RNA. 2016; 22: 696-708Crossref PubMed Scopus (4) Google Scholar). Similar analyses of protein-DNA structures allow comparison with protein-RNA interactions (Jones et al., 2001Jones S. Daley D.T.A. Luscombe N.M. Berman H.M. Thornton J.M. Protein-RNA interactions: a structural analysis.Nucleic Acids Res. 2001; 29: 943-954Crossref PubMed Google Scholar, Luscombe et al., 2001Luscombe N.M. Laskowski R.A. Thornton J.M. Amino acid-base interactions: a three-dimensional analysis of protein-DNA interactions at an atomic level.Nucleic Acids Res. 2001; 29: 2860-2874Crossref PubMed Scopus (754) Google Scholar, Wilson et al., 2016Wilson K.A. Holland D.J. Wetmore S.D. Topology of RNA-protein nucleobase-amino acid π-π interactions and comparison to analogous DNA-protein π-π contacts.RNA. 2016; 22: 696-708Crossref PubMed Scopus (4) Google Scholar). RBPs and DNA-binding proteins show many of the same preferences for interacting residues, that is, positively charged and polar residues (Hoffman et al., 2004Hoffman M.M. Khrapov M.A. Cox J.C. Yao J. Tong L. Ellington A.D. AANT: the Amino Acid-Nucleotide Interaction Database.Nucleic Acids Res. 2004; 32: D174-D181Crossref PubMed Google Scholar, Jones et al., 2001Jones S. Daley D.T.A. Luscombe N.M. Berman H.M. Thornton J.M. Protein-RNA interactions: a structural analysis.Nucleic Acids Res. 2001; 29: 943-954Crossref PubMed Google Scholar). However, the chemical and structural differences between DNA and RNA molecules result in observable differences in interactions. Approximately 20% of protein interactions with RNA occur with the 2′ OH, whereas this is not available for protein-DNA interactions (Hoffman et al., 2004Hoffman M.M. Khrapov M.A. Cox J.C. Yao J. Tong L. Ellington A.D. AANT: the Amino Acid-Nucleotide Interaction Database.Nucleic Acids Res. 2004; 32: D174-D181Crossref PubMed Google Scholar) (Figure 2). The base-pairing moieties in RNA bases are also much more extensively contacted by protein than in DNA as the Watson-Crick base face is normally base paired in DNA (Allers and Shamoo, 2001Allers J. Shamoo Y. Structure-based analysis of protein-RNA interactions using the program ENTANGLE.J. Mol. Biol. 2001; 311: 75-86Crossref PubMed Scopus (193) Google Scholar, Luscombe et al., 2001Luscombe N.M. Laskowski R.A. Thornton J.M. Amino acid-base interactions: a three-dimensional analysis of protein-DNA interactions at an atomic level.Nucleic Acids Res. 2001; 29: 2860-2874Crossref PubMed Scopus (754) Google Scholar). In this same vein, protein-DNA interactions more frequently use the phosphodiester backbone (Hoffman et al., 2004Hoffman M.M. Khrapov M.A. Cox J.C. Yao J. Tong L. Ellington A.D. AANT: the Amino Acid-Nucleotide Interaction Database.Nucleic Acids Res. 2004; 32: D174-D181Crossref PubMed Google Scholar, Jones et al., 2001Jones S. Daley D.T.A. Luscombe N.M. Berman H.M. Thornton J.M. Protein-RNA interactions: a structural analysis.Nucleic Acids Res. 2001; 29: 943-954Crossref PubMed Google Scholar). DNA-binding proteins tend to surround their target DNA helix, but this mode of binding is not always available to RBPs, which must accommodate a diver
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