Many RNA-binding proteins have a modular structure and are composed of multiple repeats of a few small domains. By arranging the domains in various ways, these proteins can satisfy the diverse biological roles they play.
The modular nature of RNA-binding proteins allows them to satisfy their functional roles in various ways. Multiple domains allow the recognition of long sequence stretches, sequences that are separated from each other or even sequences on different RNAs. The domains can pre-organize themselves to arrange the RNA in a particular topology or, conversely, the proteins can be arranged to interact with a particular RNA structure. Last, enzymatic domains can be combined with RNA-binding domains to regulate catalytic activity.
One of the most common arrangements is to have two domains separated by a short linker. This allows the protein to create a larger interaction surface that can interact with many more nucleotides than the isolated domains.
Interdomain linkers often have key functional roles in organizing the domains to facilitate the recognition of a particular substrate.
Many of the RNA-binding modules can participate in protein–protein interactions, which can facilitate assembly of higher-order complexes.
RNA-binding modules can be combined with enzymatic domains to properly position the catalytic domain on the RNA or to regulate the activity of the enzyme.
Many RNA-binding proteins have modular structures and are composed of multiple repeats of just a few basic domains that are arranged in various ways to satisfy their diverse functional requirements. Recent studies have investigated how different modules cooperate in regulating the RNA-binding specificity and the biological activity of these proteins. They have also investigated how multiple modules cooperate with enzymatic domains to regulate the catalytic activity of enzymes that act on RNA. These studies have shown how, for many RNA-binding proteins, multiple modules define the fundamental structural unit that is responsible for biological function.
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Dreyfuss, G., Kim, V. N. & Kataoka, N. Messenger-RNA-binding proteins and the messages they carry. Nature Rev. Mol. Cell Biol. 3, 195–205 (2002).
Burd, C. G. & Dreyfuss, G. Conserved structures and diversity of functions of RNA-binding proteins. Science 265, 615–621 (1994).
Auweter, S. D., Oberstrass, F. C. & Allain, F. H. Sequence-specific binding of single-stranded RNA: is there a code for recognition? Nucleic Acids Res. 34, 4943–4959 (2006). This review provides a comprehensive analysis of several RBDs and uses the recognition principles discovered in the past 10 years to construct a set of rules for RNA recognition by each domain.
Chang, K. Y. & Ramos, A. The double-stranded RNA-binding motif, a versatile macromolecular docking platform. FEBS J. 272, 2109–2117 (2005).
Hall, T. M. Multiple modes of RNA recognition by zinc finger proteins. Curr. Opin. Struct. Biol. 15, 367–373 (2005).
Maris, C., Dominguez, C. & Allain, F. H. The RNA recognition motif, a plastic RNA-binding platform to regulate post-transcriptional gene expression. FEBS J. 272, 2118–2131 (2005).
Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).
Doolittle, R. F. The multiplicity of domains in proteins. Annu. Rev. Biochem. 64, 287–314 (1995).
Bork, P., Downing, A. K., Kieffer, B. & Campbell, I. D. Structure and distribution of modules in extracellular proteins. Q. Rev. Biophys. 29, 119–167 (1996).
Sickmier, E. A. et al. Structural basis for polypyrimidine tract recognition by the essential pre-mRNA splicing factor U2AF65. Mol. Cell 23, 49–59 (2006).
Deka, P., Rajan, P. K., Perez-Canadillas, J. M. & Varani, G. Protein and RNA dynamics play key roles in determining the specific recognition of GU-rich polyadenylation regulatory elements by human Cstf-64 protein. J. Mol. Biol. 347, 719–733 (2005).
Perez Canadillas, J. M. & Varani, G. Recognition of GU-rich polyadenylation regulatory elements by human CstF-64 protein. EMBO J. 22, 2821–2830 (2003).
Allain, F. H., Bouvet, P., Dieckmann, T. & Feigon, J. Molecular basis of sequence-specific recognition of pre-ribosomal RNA by nucleolin. EMBO J. 19, 6870–6881 (2000).
Deo, R. C., Bonanno, J. B., Sonenberg, N. & Burley, S. K. Recognition of polyadenylate RNA by the poly(A)-binding protein. Cell 98, 835–845 (1999).
Handa, N. et al. Structural basis for recognition of the tra mRNA precursor by the sex-lethal protein. Nature 398, 579–585 (1999). This was among the first reports to describe what is now a common mode of RNA recognition: proteins that contain tandem RRM domains.
Perez-Canadillas, J. M. Grabbing the message: structural basis of mRNA 3′ UTR recognition by Hrp1. EMBO J. 25, 3167–3178 (2006).
Birney, E., Kumar, S. & Krainer, A. R. Analysis of the RNA-recognition motif and RS and RGG domains: conservation in metazoan pre-mRNA splicing factors. Nucleic Acids Res. 21, 5803–5816 (1993).
Oubridge, 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 372, 432–438 (1994).
Finn, R. D. et al. Pfam: clans, web tools and services. Nucleic Acids Res. 34, D247–D251 (2006).
Allain, F. H. et al. Specificity of ribonucleoprotein interaction determined by RNA folding during complex formulation. Nature 380, 646–650 (1996).
Ding, J. et al. Crystal structure of the two-RRM domain of hnRNP A1 (UP1) complexed with single-stranded telomeric DNA. Genes Dev. 13, 1102–1115 (1999).
Mazza, C., Segref, A., Mattaj, I. W. & Cusack, S. Large-scale induced fit recognition of an m(7)GpppG cap analogue by the human nuclear cap-binding complex. EMBO J. 21, 5548–5557 (2002).
Price, S. R., Evans, P. R. & Nagai, K. Crystal structure of the spliceosomal U2B″–U2A′ protein complex bound to a fragment of U2 small nuclear RNA. Nature 394, 645–650 (1998).
Varani, L. et al. The NMR structure of the 38 kDa U1A protein–PIE RNA complex reveals the basis of cooperativity in regulation of polyadenylation by human U1A protein. Nature Struct. Biol. 7, 329–335 (2000).
Wang, X. & Tanaka Hall, T. M. Structural basis for recognition of AU-rich element RNA by the HuD protein. Nature Struct. Biol. 8, 141–145 (2001). Reports the first evidence that RRMs bind RNA using a recognition mode that is highly conserved in proteins that contain single or multiple domains, providing a structural code for recognition.
Auweter, S. D. et al. Molecular basis of RNA recognition by the human alternative splicing factor Fox-1. EMBO J. 25, 163–173 (2006).
Hargous, Y. et al. Molecular basis of RNA recognition and TAP binding by the SR proteins SRp20 and 9G8. EMBO J. 25, 5126–5137 (2006).
Oberstrass, F. C. et al. Structure of PTB bound to RNA: specific binding and implications for splicing regulation. Science 309, 2054–2057 (2005). The structure of all four RRMs from PTB bound to RNA provide insight into the diverse ways in which even related domains form different RNA-recognition platforms by interacting with other RRMs in different ways.
Bono, F., Ebert, J., Lorentzen, E. & Conti, E. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell 126, 713–725 (2006).
Bono, F. et al. Molecular insights into the interaction of PYM with the Mago–Y14 core of the exon junction complex. EMBO Rep. 5, 304–310 (2004).
Fribourg, S., Gatfield, D., Izaurralde, E. & Conti, E. A novel mode of RBD-protein recognition in the Y14–Mago complex. Nature Struct. Biol. 10, 433–439 (2003).
Kadlec, J., Izaurralde, E. & Cusack, S. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nature Struct. Mol. Biol. 11, 330–337 (2004).
Kielkopf, C. L., Rodionova, N. A., Green, M. R. & Burley, S. K. A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer. Cell 106, 595–605 (2001).
Lau, C. K., Diem, M. D., Dreyfuss, G. & Van Duyne, G. D. Structure of the Y14–Magoh core of the exon junction complex. Curr. Biol. 13, 933–941 (2003).
Selenko, P. et al. Structural basis for the molecular recognition between human splicing factors U2AF65 and SF1/mBBP. Mol. Cell 11, 965–976 (2003).
Backe, P. H., Messias, A. C., Ravelli, R. B., Sattler, M. & Cusack, S. X-ray crystallographic and NMR studies of the third KH domain of hnRNP K in complex with single-stranded nucleic acids. Structure 13, 1055–1067 (2005).
Beuth, B., Pennell, S., Arnvig, K. B., Martin, S. R. & Taylor, I. A. Structure of a Mycobacterium tuberculosis NusA–RNA complex. EMBO J. 24, 3576–3587 (2005).
Braddock, D. T., Baber, J. L., Levens, D. & Clore, G. M. Molecular basis of sequence-specific single-stranded DNA recognition by KH domains: solution structure of a complex between hnRNP K KH3 and single-stranded DNA. EMBO J. 21, 3476–3485 (2002).
Braddock, D. T., Louis, J. M., Baber, J. L., Levens, D. & Clore, G. M. Structure and dynamics of KH domains from FBP bound to single-stranded DNA. Nature 415, 1051–1056 (2002).
Du, Z. et al. Crystal structure of the first KH domain of human poly(C)-binding protein-2 in complex with a C-rich strand of human telomeric DNA at 1.7 Å. J. Biol. Chem. 280, 38823–38830 (2005).
Lewis, H. A. et al. Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome. Cell 100, 323–332 (2000).
Liu, Z. et al. Structural basis for recognition of the intron branch site RNA by splicing factor 1. Science 294, 1098–1102 (2001).
Siomi, H., Matunis, M. J., Michael, W. M. & Dreyfuss, G. The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. Nucleic Acids Res. 21, 1193–1198 (1993).
De Boulle, K. et al. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genet. 3, 31–35 (1993).
Grishin, N. V. KH domain: one motif, two folds. Nucleic Acids Res. 29, 638–643 (2001).
Ryter, J. M. & Schultz, S. C. Molecular basis of double-stranded RNA-protein interactions: structure of a dsRNA-binding domain complexed with dsRNA. EMBO J. 17, 7505–7513 (1998).
Stephens, O. M., Haudenschild, B. L. & Beal, P. A. The binding selectivity of ADAR2's dsRBMs contributes to RNA-editing selectivity. Chem. Biol. 11, 1239–1250 (2004).
Stefl, R., Xu, M., Skrisovska, L., Emeson, R. B. & Allain, F. H. Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure 14, 345–355 (2006).
Xu, M., Wells, K. S. & Emeson, R. B. Substrate-dependent contribution of double-stranded RNA-binding motifs to ADAR2 function. Mol. Biol. Cell 17, 3211–3220 (2006).
Leulliot, N. et al. A new α-helical extension promotes RNA binding by the dsRBD of Rnt1p RNAse III. EMBO J. 23, 2468–2477 (2004).
Ramos, A. et al. RNA recognition by a Staufen double-stranded RNA-binding domain. EMBO J. 19, 997–1009 (2000).
Wu, H., Henras, A., Chanfreau, G. & Feigon, J. Structural basis for recognition of the AGNN tetraloop RNA fold by the double-stranded RNA-binding domain of Rnt1p RNase III. Proc. Natl Acad. Sci. USA 101, 8307–8312 (2004).
Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281, 1001–1005 (1998).
Picard, B. & Wegnez, M. Isolation of a 7S particle from Xenopus laevis oocytes: a 5S RNA–protein complex. Proc. Natl Acad. Sci. USA 76, 241–245 (1979).
Lee, B. M. et al. Induced fit and “lock and key” recognition of 5S RNA by zinc fingers of transcription factor IIIA. J. Mol. Biol. 357, 275–291 (2006).
Lu, D., Searles, M. A. & Klug, A. Crystal structure of a zinc-finger-RNA complex reveals two modes of molecular recognition. Nature 426, 96–100 (2003). This structure provides the first example of a zinc-finger protein bound to RNA, and also shows how an entire domain can function as a linker to position zinc fingers 4 and 6 for recognition of their respective binding sites and space them as needed.
Hudson, B. P., Martinez-Yamout, M. A., Dyson, H. J. & Wright, P. E. Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d. Nature Struct. Mol. Biol. 11, 257–264 (2004).
Clemens, K. R. et al. Molecular basis for specific recognition of both RNA and DNA by a zinc finger protein. Science 260, 530–533 (1993).
Searles, M. A., Lu, D. & Klug, A. The role of the central zinc fingers of transcription factor IIIA in binding to 5 S RNA. J. Mol. Biol. 301, 47–60 (2000).
Wolfe, S. A., Nekludova, L. & Pabo, C. O. DNA recognition by Cys2His2 zinc finger proteins. Annu. Rev. Biophys. Biomol. Struct. 29, 183–212 (2000).
Lai, W. S., Carballo, E., Thorn, J. M., Kennington, E. A. & Blackshear, P. J. Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to AU-rich elements and destabilization of mRNA. J. Biol. Chem. 275, 17827–17837 (2000).
D'Souza, V. & Summers, M. F. Structural basis for packaging the dimeric genome of Moloney murine leukaemia virus. Nature 431, 586–590 (2004).
De Guzman, R. N. et al. Structure of the HIV-1 nucleocapsid protein bound to the SL3 psi-RNA recognition element. Science 279, 384–388 (1998).
Subramanian, A. R. Structure and functions of ribosomal protein S1. Prog. Nucleic Acid Res. Mol. Biol. 28, 101–142 (1983).
Bycroft, M., Hubbard, T. J., Proctor, M., Freund, S. M. & Murzin, A. G. The solution structure of the S1 RNA binding domain: a member of an ancient nucleic acid-binding fold. Cell 88, 235–242 (1997).
Murzin, A. G. OB (oligonucleotide/oligosaccharide binding)-fold: common structural and functional solution for non-homologous sequences. EMBO J. 12, 861–867 (1993).
Arcus, V. OB-fold domains: a snapshot of the evolution of sequence, structure and function. Curr. Opin. Struct. Biol. 12, 794–801 (2002).
Schubert, M. et al. Structural characterization of the RNase E S1 domain and identification of its oligonucleotide-binding and dimerization interfaces. J. Mol. Biol. 341, 37–54 (2004).
Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain. Nature 426, 465–469 (2003).
Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. Nucleic acid 3′-end recognition by the Argonaute2 PAZ domain. Nature Struct. Mol. Biol. 11, 576–577 (2004).
Yan, K. S. et al. Structure and conserved RNA binding of the PAZ domain. Nature 426, 468–474 (2003).
Macrae, I. J. et al. Structural basis for double-stranded RNA processing by Dicer. Science 311, 195–198 (2006).
Ma, J. B., Ye, K. & Patel, D. J. Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain. Nature 429, 318–322 (2004).
Yuan, Y. R. et al. Crystal structure of A. aeolicus argonaute, a site-specific DNA-guided endoribonuclease, provides insights into RISC-mediated mRNA cleavage. Mol. Cell 19, 405–419 (2005).
Ma, J. B. et al. Structural basis for 5′-end-specific recognition of guide RNA by the A. fulgidus Piwi protein. Nature 434, 666–670 (2005).
Song, J. J., Smith, S. K., Hannon, G. J. & Joshua-Tor, L. Crystal structure of Argonaute and its implications for RISC slicer activity. Science 305, 1434–1437 (2004).
Parker, J. S., Roe, S. M. & Barford, D. Crystal structure of a PIWI protein suggests mechanisms for siRNA recognition and slicer activity. EMBO J. 23, 4727–4737 (2004).
Parker, J. S., Roe, S. M. & Barford, D. Structural insights into mRNA recognition from a PIWI domain–siRNA guide complex. Nature 434, 663–666 (2005).
Dominguez, C. & Allain, F. H. NMR structure of the three quasi RNA recognition motifs (qRRMs) of human hnRNP F and interaction studies with Bcl-x G-tract RNA: a novel mode of RNA recognition. Nucleic Acids Res. 34, 3634–3645 (2006).
Swanson, M. S. & Dreyfuss, G. Classification and purification of proteins of heterogeneous nuclear ribonucleoprotein particles by RNA-binding specificities. Mol. Cell. Biol. 8, 2237–2241 (1988).
McCullough, A. J. & Berget, S. M. G triplets located throughout a class of small vertebrate introns enforce intron borders and regulate splice site selection. Mol. Cell. Biol. 17, 4562–4571 (1997).
Garneau, D., Revil, T., Fisette, J. F. & Chabot, B. Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x. J. Biol. Chem. 280, 22641–22650 (2005).
Jacks, A. et al. Structure of the C-terminal domain of human La protein reveals a novel RNA recognition motif coupled to a helical nuclear retention element. Structure 11, 833–843 (2003).
Wang, X., McLachlan, J., Zamore, P. D. & Hall, T. M. Modular recognition of RNA by a human Pumilio-homology domain. Cell 110, 501–512 (2002). This work beautifully illustrates how a protein can use multiple repeated structural motifs to create specific, high-affinity interactions with RNA; each domain binds a single nucleotide, but the combination of multiple domains provides exquisite specificity.
Cheong, C. G. & Hall, T. M. Engineering RNA sequence specificity of Pumilio repeats. Proc. Natl Acad. Sci. USA 103, 13635–13639 (2006). Building on reference 84, this work introduces a reasonably predictive recognition code for this family of RNA-binding proteins that allows rational engineering of specificity.
Worbs, M., Bourenkov, G. P., Bartunik, H. D., Huber, R. & Wahl, M. C. An extended RNA binding surface through arrayed S1 and KH domains in transcription factor NusA. Mol. Cell 7, 1177–1189 (2001).
Shamoo, Y., Abdul-Manan, N. & Williams, K. R. Multiple RNA binding domains (RBDs) just don't add up. Nucleic Acids Res. 23, 725–728 (1995). This work examines in quantitative detail the importance of the linker in recognition of an RNA and provides a simple method for predicting the affinity of two RRMs separated by a linker of variable length.
Shamoo, Y. et al. Both RNA-binding domains in heterogenous nuclear ribonucleoprotein A1 contribute toward single-stranded-RNA binding. Biochemistry 33, 8272–8281 (1994).
Finger, L. D., Johansson, C., Rinaldi, B., Bouvet, P. & Feigon, J. Contributions of the RNA-binding and linker domains and RNA structure to the specificity and affinity of the nucleolin RBD12/NRE interaction. Biochemistry 43, 6937–6947 (2004).
Lakatos, L., Szittya, G., Silhavy, D. & Burgyan, J. Molecular mechanism of RNA silencing suppression mediated by p19 protein of tombusviruses. EMBO J. 23, 876–884 (2004).
Dunoyer, P., Lecellier, C. H., Parizotto, E. A., Himber, C. & Voinnet, O. Probing the microRNA and small interfering RNA pathways with virus-encoded suppressors of RNA silencing. Plant Cell 16, 1235–1250 (2004).
Vargason, J. M., Szittya, G., Burgyan, J. & Tanaka Hall, T. M. Size selective recognition of siRNA by an RNA silencing suppressor. Cell 115, 799–811 (2003).
Ye, K., Malinina, L. & Patel, D. J. Recognition of small interfering RNA by a viral suppressor of RNA silencing. Nature 426, 874–878 (2003).
Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. The structure of the flock house virus B2 protein, a viral suppressor of RNA interference, shows a novel mode of double-stranded RNA recognition. EMBO Rep. 6, 1149–1155 (2005).
Chao, J. A. et al. Dual modes of RNA-silencing suppression by Flock House virus protein B2. Nature Struct. Mol. Biol. 12, 952–957 (2005).
Ramos, A. et al. Role of dimerization in KH/RNA complexes: the example of Nova KH3. Biochemistry 41, 4193–4201 (2002).
Calero, G. et al. Structural basis of m7GpppG binding to the nuclear cap-binding protein complex. Nature Struct. Biol. 9, 912–917 (2002).
Buttner, K., Wenig, K. & Hopfner, K. P. Structural framework for the mechanism of archaeal exosomes in RNA processing. Mol. Cell 20, 461–471 (2005).
Liu, Q., Greimann, J. C. & Lima, C. D. Reconstitution, activities, and structure of the eukaryotic RNA exosome. Cell 127, 1223–1237 (2006). This beautiful structure provides a number of examples of protein–protein interactions between S1 and KH domains at the core of the exosome.
Abovich, N. & Rosbash, M. Cross-intron bridging interactions in the yeast commitment complex are conserved in mammals. Cell 89, 403–412 (1997).
Michaud, S. & Reed, R. An ATP-independent complex commits pre-mRNA to the mammalian spliceosome assembly pathway. Genes Dev. 5, 2534–2546 (1991).
Zamore, P. D., Patton, J. G. & Green, M. R. Cloning and domain structure of the mammalian splicing factor U2AF. Nature 355, 609–614 (1992).
Kielkopf, C. L., Lucke, S. & Green, M. R. U2AF homology motifs: protein recognition in the RRM world. Genes Dev. 18, 1513–1526 (2004).
Andersen, C. B. et al. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA. Science 313, 1968–1972 (2006).
Stroupe, M. E., Tange, T. O., Thomas, D. R., Moore, M. J. & Grigorieff, N. The three-dimensional architecture of the EJC core. J. Mol. Biol. 360, 743–749 (2006).
Irion, U., Adams, J., Chang, C. W. & St Johnston, D. Miranda couples oskar mRNA/Staufen complexes to the bicoid mRNA localization pathway. Dev. Biol. 297, 522–533 (2006).
Collins, R. E. & Cheng, X. Structural domains in RNAi. FEBS Lett. 579, 5841–5849 (2005).
Li, L. & Ye, K. Crystal structure of an H/ACA box ribonucleoprotein particle. Nature 443, 302–307 (2006).
Reichow, S. L., Hamma, T., Ferre-D'Amare, A. R. & Varani, G. The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Res. 35, 1452–1464 (2007).
Williams, B. R. PKR; a sentinel kinase for cellular stress. Oncogene 18, 6112–6120 (1999).
Bass, B. L. RNA editing by adenosine deaminases that act on RNA. Annu. Rev. Biochem. 71, 817–846 (2002).
Nanduri, S., Rahman, F., Williams, B. R. & Qin, J. A dynamically tuned double-stranded RNA binding mechanism for the activation of antiviral kinase PKR. EMBO J. 19, 5567–5574 (2000). This work demonstrates how the second dsRBD of the dsRNA-activated kinase PKR interacts with the C-terminal kinase domain, maintaining it in an inhibited state.
Macbeth, M. R., Lingam, A. T. & Bass, B. L. Evidence for auto-inhibition by the N terminus of hADAR2 and activation by dsRNA binding. RNA 10, 1563–1571 (2004).
Gelev, V. et al. Mapping of the auto-inhibitory interactions of protein kinase R by nuclear magnetic resonance. J. Mol. Biol. 364, 352–363 (2006).
Li, S. et al. Molecular basis for PKR activation by PACT or dsRNA. Proc. Natl Acad. Sci. USA 103, 10005–10010 (2006).
Bevilacqua, P. C. & Cech, T. R. Minor-groove recognition of double-stranded RNA by the double-stranded RNA-binding domain from the RNA-activated protein kinase PKR. Biochemistry 35, 9983–9994 (1996).
Kim, I., Liu, C. W. & Puglisi, J. D. Specific recognition of HIV TAR RNA by the dsRNA binding domains (dsRBD1–dsRBD2) of PKR. J. Mol. Biol. 358, 430–442 (2006).
Carpick, B. W. et al. Characterization of the solution complex between the interferon-induced, double-stranded RNA-activated protein kinase and HIV-I trans-activating region RNA. J. Biol. Chem. 272, 9510–9516 (1997).
Romano, P. R. et al. Autophosphorylation in the activation loop is required for full kinase activity in vivo of human and yeast eukaryotic initiation factor 2α kinases PKR and GCN2. Mol. Cell. Biol. 18, 2282–2297 (1998).
Zhang, F. et al. Binding of double-stranded RNA to protein kinase PKR is required for dimerization and promotes critical autophosphorylation events in the activation loop. J. Biol. Chem. 276, 24946–24958 (2001).
Frazao, C. et al. Unravelling the dynamics of RNA degradation by ribonuclease II and its RNA-bound complex. Nature 443, 110–114 (2006).
Antson, A. A. et al. Structure of the trp RNA-binding attenuation protein, TRAP, bound to RNA. Nature 401, 235–242 (1999).
Oberstrass, F. C. et al. Shape-specific recognition in the structure of the Vts1p SAM domain with RNA. Nature Struct. Mol. Biol. 13, 160–167 (2006).
Work in our laboratories is supported by grants from National Institutes of Health–National Institute of General Medical Sciences (G.V. and C.M.). We apologize to the many colleagues whose work could not be properly referenced owing to lack of space.
The authors declare no competing financial interests.
(RNP). A complex that contains proteins and RNA. The RNP motif refers to the two conserved sequence elements found in the RNA-recognition motif (RRM) (in its two central β-strands) that participate in RNA recognition and identify the RRM domain at the sequence level.
- Orthologous proteins
Proteins that are direct evolutionary counterparts, that retain the same function in different organisms and that have arisen due to speciation events but not through the process of gene duplication (paralogous proteins).
- Zinc finger
A class of DNA- and RNA-binding proteins characterized by a Cys- and His-rich domain that chelates a zinc ion. Different classes of zinc-finger proteins contain different combinations of metal-binding amino acids: CCHH zinc fingers contain two Cys and two His residues, whereas CCCH and CCHC zinc-binding motifs contain three Cys and a single His residue in different topological arrangements.
- AU-rich element
Sequences rich in A and U nucleotides that are found in the 3′ untranslated regions of mRNAs that promote stability or degradation of their associated RNAs, thus providing a mechanism for the control of gene expression.
- Argonaute proteins
A family of proteins that are characterized by the presence of two homology domains, PAZ and PIWI. The proteins provide the essential catalytic activity for diverse RNA-silencing pathways.
- RNA-induced silencing complex
A multicomponent ribonucleoprotein complex that cleaves specific mRNAs that are targeted for degradation by homologous double-stranded RNAs during the process of RNA interference.
- Pumilio (Puf) family of proteins
A highly conserved family of RNA-binding proteins with a C-terminal RNA-binding domain that is composed of eight tandem repeats, with each repeat recognizing a single nucleotide.
A multisubunit 3′→5′ exonuclease that functions in the nucleus and the cytoplasm in several different RNA-processing and RNA-degradation pathways.
- Exon-junction complex
A multisubunit protein complex that is deposited on the mRNA during the splicing reaction near the splice site. It remains bound to the RNA during subsequent gene-expression events, and serves as a platform to recruit nuclear and cytoplasmic factors that influence mRNA localization, transport, stability and translation.
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Lunde, B., Moore, C. & Varani, G. RNA-binding proteins: modular design for efficient function. Nat Rev Mol Cell Biol 8, 479–490 (2007). https://doi.org/10.1038/nrm2178
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