RNA recognition by double-stranded RNA binding domains: a matter of shape and sequence

The double-stranded RNA binding domain (dsRBD) is a small protein domain of 65–70 amino acids adopting an αβββα fold, whose central property is to bind to double-stranded RNA (dsRNA). This domain is present in proteins implicated in many aspects of cellular life, including antiviral response, RNA editing, RNA processing, RNA transport and, last but not least, RNA silencing. Even though proteins containing dsRBDs can bind to very specific dsRNA targets in vivo, the binding of dsRBDs to dsRNA is commonly believed to be shape-dependent rather than sequence-specific. Interestingly, recent structural information on dsRNA recognition by dsRBDs opens the possibility that this domain performs a direct readout of RNA sequence in the minor groove, allowing a global reconsideration of the principles describing dsRNA recognition by dsRBDs. We review in this article the current structural and molecular knowledge on dsRBDs, emphasizing the intricate relationship between the amino acid sequence, the structure of the domain and its RNA recognition capacity. We especially focus on the molecular determinants of dsRNA recognition and describe how sequence discrimination can be achieved by this type of domain.

[1]  W. Toone,et al.  Mutational Analysis of the Double-stranded RNA (dsRNA) Binding Domain of the dsRNA-activated Protein Kinase, PKR (*) , 1995, The Journal of Biological Chemistry.

[2]  M. Mathews,et al.  Two RNA-binding motifs in the double-stranded RNA-activated protein kinase, DAI. , 1992, Genes & development.

[3]  Rekha C. Patel,et al.  The carboxy-terminal, M3 motifs of PACT and TRBP have opposite effects on PKR activity. , 2003, Virology.

[4]  A. Caudy,et al.  Role for a bidentate ribonuclease in the initiation step of RNA interference , 2001 .

[5]  R. Stefl,et al.  RNA sequence‐ and shape‐dependent recognition by proteins in the ribonucleoprotein particle , 2005, EMBO reports.

[6]  F. Allain,et al.  Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. , 2006, Structure.

[7]  N. Seeman,et al.  Sequence-specific Recognition of Double Helical Nucleic Acids by Proteins (base Pairs/hydrogen Bonding/recognition Fidelity/ion Binding) , 2022 .

[8]  C Combet,et al.  NPS@: network protein sequence analysis. , 2000, Trends in biochemical sciences.

[9]  D. Draper,et al.  Protein-RNA recognition. , 1995, Annual review of biochemistry.

[10]  Sherif Abou Elela,et al.  Structure of an AAGU tetraloop and its contribution to substrate selection by yeast RNase III. , 2006, Journal of molecular biology.

[11]  A. Nicholson,et al.  Characterization of RNA sequence determinants and antideterminants of processing reactivity for a minimal substrate of Escherichia coli ribonuclease III , 2006, Nucleic acids research.

[12]  J. Rosenthal,et al.  Functional conservation in human and Drosophila of Metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects , 2011 .

[13]  M. Ares,et al.  A new alpha-helical extension promotes RNA binding by the dsRBD of Rnt1p RNAse III. , 2004, The EMBO journal.

[14]  D. Feldmeyer,et al.  Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2 , 2000, Nature.

[15]  G. Struhl,et al.  Cis- acting sequences responsible for anterior localization of bicoid mRNA in Drosophila embryos , 1988, Nature.

[16]  C. Dominguez,et al.  The RNA recognition motif, a plastic RNA‐binding platform to regulate post‐transcriptional gene expression , 2005, The FEBS journal.

[17]  Brenda L Bass,et al.  RNA editing by adenosine deaminases that act on RNA. , 2002, Annual review of biochemistry.

[18]  M. Mathews,et al.  Two functionally distinct RNA-binding motifs in the regulatory domain of the protein kinase DAI , 1995, Molecular and cellular biology.

[19]  B. Williams,et al.  Structure of the double‐stranded RNA‐binding domain of the protein kinase PKR reveals the molecular basis of its dsRNA‐mediated activation , 1998, The EMBO journal.

[20]  A. Murzin,et al.  NMR solution structure of a dsRNA binding domain from Drosophila staufen protein reveals homology to the N‐terminal domain of ribosomal protein S5. , 1995, The EMBO journal.

[21]  K. Hall,et al.  RNA-protein interactions. , 2002, Current opinion in structural biology.

[22]  G. Barber,et al.  The dsRNA binding protein family: critical roles, diverse cellular functions , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  A. Nicholson.  Ribonuclease III and the Role of Double-Stranded RNA Processing in Bacterial Systems , 2011 .

[24]  Sherif Abou Elela,et al.  A Physical Interaction between Gar1p and Rnt1p Is Required for the Nuclear Import of H/ACA Small Nucleolar RNA-Associated Proteins , 2002, Molecular and Cellular Biology.

[25]  S C Schultz,et al.  Molecular basis of double‐stranded RNA‐protein interactions: structure of a dsRNA‐binding domain complexed with dsRNA , 1998, The EMBO journal.

[26]  Gabriele Varani,et al.  RNA recognition by a Staufen double‐stranded RNA‐binding domain , 2000, The EMBO journal.

[27]  M. Buckle,et al.  Recognition of a conserved class of RNA tetraloops by Saccharomyces cerevisiae RNase III. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Gabriele Varani,et al.  Protein families and RNA recognition , 2005, The FEBS journal.

[29]  E. Sontheimer,et al.  Origins and Mechanisms of miRNAs and siRNAs , 2009, Cell.

[30]  G. Chanfreau.  Conservation of RNase III Processing Pathways and Specificity in Hemiascomycetes , 2003, Eukaryotic Cell.

[31]  G. Feng,et al.  Identification of double-stranded RNA-binding domains in the interferon-induced double-stranded RNA-activated p68 kinase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. St Johnston,et al.  A conserved double-stranded RNA-binding domain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[33]  D. Draper.  Themes in RNA-protein recognition. , 1999, Journal of molecular biology.

[34]  Tzvi Aviv,et al.  Sequence-specific recognition of RNA hairpins by the SAM domain of Vts1p , 2006, Nature Structural &Molecular Biology.

[35]  J. Boisbouvier,et al.  Structure and RNA interactions of the plant MicroRNA processing-associated protein HYL1. , 2010, Biochemistry.

[36]  P. Seeburg,et al.  RNA editing of AMPA receptor subunit GluR-B: A base-paired intron-exon structure determines position and efficiency , 1993, Cell.

[37]  Aaron Klug,et al.  Crystal structure of a zinc-finger–RNA complex reveals two modes of molecular recognition , 2003, Nature.

[38]  S. P. Walton,et al.  Recognition of siRNA asymmetry by TAR RNA binding protein. , 2010, Biochemistry.

[39]  K. A. Lehmann,et al.  Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. , 2000, Biochemistry.

[40]  Jochen C. Hartner,et al.  Role of ADARs in mouse development. , 2012, Current topics in microbiology and immunology.

[41]  D. Court,et al.  Noncatalytic assembly of ribonuclease III with double-stranded RNA. , 2004, Structure.

[42]  G. Varani.  Exceptionally stable nucleic acid hairpins. , 1995, Annual review of biophysics and biomolecular structure.

[43]  A. Nicholson,et al.  Regulation of ribonuclease III processing by double-helical sequence antideterminants. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Sherif Abou Elela,et al.  Solution structure of conserved AGNN tetraloops: insights into Rnt1p RNA processing , 2001, EMBO Journal.

[45]  Anthony Henras,et al.  Structural basis for recognition of the AGNN tetraloop RNA fold by the double-stranded RNA-binding domain of Rnt1p RNase III. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Kiebler,et al.  Mechanisms of dendritic mRNA transport and its role in synaptic tagging , 2011, The EMBO journal.

[47]  Wolfram Saenger,et al.  Principles of Nucleic Acid Structure , 1983 .

[48]  P. Güntert,et al.  Structures of the first and second double‐stranded RNA‐binding domains of human TAR RNA‐binding protein , 2011, Protein science : a publication of the Protein Society.

[49]  M. Jantsch,et al.  RNA-Regulated Interaction of Transportin-1 and Exportin-5 with the Double-Stranded RNA-Binding Domain Regulates Nucleocytoplasmic Shuttling of ADAR1 , 2009, Molecular and Cellular Biology.

[50]  Sherif Abou Elela,et al.  The RNase III family: a conserved structure and expanding functions in eukaryotic dsRNA metabolism. , 2001, Current issues in molecular biology.

[51]  M. Ares,et al.  A new α‐helical extension promotes RNA binding by the dsRBD of Rnt1p RNAse III , 2004 .

[52]  A. Nicholson.  Function, mechanism and regulation of bacterial ribonucleases. , 1999, FEMS microbiology reviews.

[53]  Qixing Huang,et al.  Structural insights into mechanisms of the small RNA methyltransferase HEN1 , 2009, Nature.

[54]  A. Nicholson,et al.  Thermotoga maritima ribonuclease III. Characterization of thermostable biochemical behavior and analysis of conserved base pairs that function as reactivity epitopes for the Thermotoga 23S rRNA precursor. , 2010, Biochemistry.

[55]  T. Hall,et al.  Multiple modes of RNA recognition by zinc finger proteins. , 2005, Current opinion in structural biology.

[56]  Raymond S Brown,et al.  Zinc finger proteins: getting a grip on RNA. , 2005, Current opinion in structural biology.

[57]  C. Doe,et al.  Staufen-dependent localization of prospero mRNA contributes to neuroblast daughter-cell fate , 1998, Nature.

[58]  Anne Gatignol,et al.  TRBP, a regulator of cellular PKR and HIV‐1 virus expression, interacts with Dicer and functions in RNA silencing , 2005, EMBO reports.

[59]  Catherine Dargemont,et al.  Minihelix-containing RNAs Mediate Exportin-5-dependent Nuclear Export of the Double-stranded RNA-binding Protein ILF3* , 2004, Journal of Biological Chemistry.

[60]  A. Rich,et al.  Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA. , 1999, Science.

[61]  A. Rich,et al.  A left-handed RNA double helix bound by the Z alpha domain of the RNA-editing enzyme ADAR1. , 2007, Structure.

[62]  K. Nishikura.  Functions and regulation of RNA editing by ADAR deaminases. , 2010, Annual review of biochemistry.

[63]  T. Steitz,et al.  Structural studies of protein–nucleic acid interaction: the sources of sequence-specific binding , 1990, Quarterly Reviews of Biophysics.

[64]  T. Cech,et al.  Minor-groove recognition of double-stranded RNA by the double-stranded RNA-binding domain from the RNA-activated protein kinase PKR. , 1996, Biochemistry.

[65]  J. L. Smith,et al.  Multiple RNA regulatory elements mediate distinct steps in localization of oskar mRNA. , 1993, Development.

[66]  D. Court,et al.  Intermediate states of ribonuclease III in complex with double-stranded RNA. , 2005, Structure.

[67]  F. Allain,et al.  Molecular basis of sequence‐specific recognition of pre‐ribosomal RNA by nucleolin , 2000, The EMBO journal.

[68]  Yuasa Takashi,et al.  The interaction between DCL1 and HYL1 is important for efficient and precise processing of pri-miRNA in plant microRNA biogenesis. , 2005, RNA.

[69]  M. Ghosh,et al.  Solution structure of the Drosha double-stranded RNA-binding domain , 2010, Silence.

[70]  D. Court,et al.  Structural Insight into the Mechanism of Double-Stranded RNA Processing by Ribonuclease III , 2006, Cell.

[71]  A. Nicholson,et al.  Characterization of Aquifex aeolicus ribonuclease III and the reactivity epitopes of its pre-ribosomal RNA substrates , 2010, Nucleic acids research.

[72]  D. St Johnston,et al.  Dimerization of the 3'UTR of bicoid mRNA involves a two-step mechanism. , 2001, Journal of molecular biology.

[73]  G. Sen,et al.  PACT, a protein activator of the interferon‐induced protein kinase, PKR , 1998, The EMBO journal.

[74]  Florian C. Oberstrass,et al.  Shape-specific recognition in the structure of the Vts1p SAM domain with RNA , 2006, Nature Structural &Molecular Biology.

[75]  Sherif Abou Elela,et al.  Characterization of the reactivity determinants of a novel hairpin substrate of yeast RNase III. , 2006, Journal of molecular biology.

[76]  C R Woese,et al.  Architecture of ribosomal RNA: constraints on the sequence of "tetra-loops". , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[77]  H R Drew,et al.  The anatomy of A-, B-, and Z-DNA. , 1982, Science.

[78]  M. Ares,et al.  Substrate recognition by a eukaryotic RNase III: the double-stranded RNA-binding domain of Rnt1p selectively binds RNA containing a 5'-AGNN-3' tetraloop. , 2000, RNA.

[79]  T. Gibson,et al.  Structure of the dsRNA binding domain of E. coli RNase III. , 1995, The EMBO journal.

[80]  G. Sen,et al.  Specific Mutations Near the Amino Terminus of Double-stranded RNA-dependent Protein Kinase (PKR) Differentially Affect Its Double-stranded RNA Binding and Dimerization Properties* , 1996, The Journal of Biological Chemistry.

[81]  H. Hotz,et al.  RNAi keeps Atf1-bound stress response genes in check at nuclear pores. , 2012, Genes & development.

[82]  M. Mathews,et al.  Proteins binding to duplexed RNA: one motif, multiple functions. , 2000, Trends in biochemical sciences.

[83]  D. St Johnston,et al.  Distinct roles of two conserved Staufen domains in oskar mRNA localization and translation , 2000, The EMBO journal.

[84]  Zhihua Du,et al.  Structural and biochemical insights into the dicing mechanism of mouse Dicer: A conserved lysine is critical for dsRNA cleavage , 2008, Proceedings of the National Academy of Sciences.

[85]  Dominique Ferrandon,et al.  Staufen protein associates with the 3′UTR of bicoid mRNA to form particles that move in a microtubule-dependent manner , 1994, Cell.

[86]  M. O’Connell,et al.  Regulation and functions of ADAR in drosophila. , 2012, Current topics in microbiology and immunology.

[87]  F. Allain,et al.  Solution structure of the N-terminal dsRBD of Drosophila ADAR and interaction studies with RNA. , 2012, Biochimie.

[88]  Michael B. Mathews,et al.  The double-stranded-RNA-binding motif: interference and much more , 2004, Nature Reviews Molecular Cell Biology.

[89]  D. St Johnston,et al.  Miranda mediates asymmetric protein and RNA localization in the developing nervous system. , 1998, Genes & development.

[90]  M. Bühler,et al.  Nuclear retention of fission yeast dicer is a prerequisite for RNAi-mediated heterochromatin assembly. , 2010, Developmental cell.

[91]  Frédéric H.-T. Allain,et al.  The Solution Structure of the ADAR2 dsRBM-RNA Complex Reveals a Sequence-Specific Readout of the Minor Groove , 2010, Cell.

[92]  B. Berkhout,et al.  Characterization of a human TAR RNA-binding protein that activates the HIV-1 LTR. , 1991, Science.

[93]  Luc DesGroseillers,et al.  The Brain-specific Double-stranded RNA-binding Protein Staufen2 , 2004, Journal of Biological Chemistry.

[94]  G. Varani,et al.  Specificity of ribonucleoprotein interaction determined by RNA folding during complex formation , 1996, Nature.

[95]  D. Court,et al.  A stepwise model for double‐stranded RNA processing by ribonuclease III , 2007, Molecular microbiology.

[96]  M. Hallegger,et al.  Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain. , 2002, Molecular biology of the cell.

[97]  Yunje Cho,et al.  Crystal structure of human DGCR8 core , 2007, Nature Structural &Molecular Biology.

[98]  A. Pasquinelli,et al.  A Cellular Function for the RNA-Interference Enzyme Dicer in the Maturation of the let-7 Small Temporal RNA , 2001, Science.

[99]  I. Macara,et al.  Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins , 2002, The Journal of cell biology.

[100]  Peter J. Bickel,et al.  The Developmental Transcriptome of Drosophila melanogaster , 2010, Nature.

[101]  P. Güntert,et al.  Solution structures of the double‐stranded RNA‐binding domains from rna helicase A , 2012, Proteins.

[102]  H. Hotz,et al.  An extended dsRBD with a novel zinc-binding motif mediates nuclear retention of fission yeast Dicer , 2011, The EMBO journal.

[103]  A. Hinnebusch,et al.  Binding of Double-stranded RNA to Protein Kinase PKR Is Required for Dimerization and Promotes Critical Autophosphorylation Events in the Activation Loop* , 2001, The Journal of Biological Chemistry.

[104]  Philipp Wenter,et al.  The testis‐specific human protein RBMY recognizes RNA through a novel mode of interaction , 2007, EMBO reports.

[105]  M. Jantsch,et al.  Oligomerization activity of a double‐stranded RNA‐binding domain , 2004, FEBS letters.

[106]  C. Carlson,et al.  Recognition of double-stranded RNA by proteins and small molecules. , 2003, Biopolymers.

[107]  Nobutoshi Ito,et al.  Crystal structure at 1.92 Å resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin , 1994, Nature.

[108]  A. Rich,et al.  A Left-Handed RNA Double Helix Bound by the Zα Domain of the RNA-Editing Enzyme ADAR1 , 2007 .

[109]  D. Bartel,et al.  The Inside-Out Mechanism of Dicers from Budding Yeasts , 2011, Cell.

[110]  F. Allain,et al.  ADAR proteins: double-stranded RNA and Z-DNA binding domains. , 2012, Current topics in microbiology and immunology.

[111]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[112]  N. Chua,et al.  Structure of Arabidopsis HYPONASTIC LEAVES1 and its molecular implications for miRNA processing. , 2010, Structure.

[113]  R. Reenan,et al.  A-to-I Pre-mRNA Editing in Drosophila Is Primarily Involved in Adult Nervous System Function and Integrity , 2000, Cell.

[114]  J. Feigon,et al.  A novel family of RNA tetraloop structure forms the recognition site for Saccharomyces cerevisiae RNase III , 2001, The EMBO journal.

[115]  R. Reenan,et al.  Tuning of RNA editing by ADAR is required in Drosophila , 2005, The EMBO journal.

[116]  F. Corpet.  Multiple sequence alignment with hierarchical clustering. , 1988, Nucleic acids research.

[117]  M. Jantsch,et al.  Comparative Mutational Analysis of the Double-stranded RNA Binding Domains of Xenopus laevis RNA-binding Protein A* , 1996, The Journal of Biological Chemistry.

[118]  Andres Ramos,et al.  The double‐stranded RNA‐binding motif, a versatile macromolecular docking platform , 2005, The FEBS journal.

[119]  C. Samuel,et al.  Mechanism of interferon action: identification of a RNA binding domain within the N-terminal region of the human RNA-dependent P1/eIF-2 alpha protein kinase. , 1992, Virology.

[120]  J. Feigon,et al.  Structure of a yeast RNase III dsRBD complex with a noncanonical RNA substrate provides new insights into binding specificity of dsRBDs. , 2011, Structure.