title: Substrate recognition and specificity of double-stranded RNA binding proteins.
abstract: Recognition of double-stranded (ds) RNA is an important part of many cellular pathways, including RNA silencing, viral recognition, RNA editing, processing, and transport. dsRNA recognition is often achieved by dsRNA binding domains (dsRBDs). We use atomistic molecular dynamics simulations to examine the binding interface of the transactivation response RNA binding protein (TRBP) dsRBDs to dsRNA substrates. Our results explain the exclusive selectivity of dsRBDs toward dsRNA and against DNA-RNA hybrid and dsDNA duplexes. We also provide corresponding experimental evidence. The dsRNA duplex is recognized by dsRBDs through the A-form of three duplex grooves and by the chemical properties of RNA bases, which have 2'-hydroxyl groups on their sugar rings. Our simulations show that TRBP dsRBD discriminates dsRNA- from DNA-containing duplexes primarily through interactions at two duplex grooves. The simulations also reveal that the conformation of the DNA-RNA duplex can be altered by dsRBD proteins, resulting in a weak binding of dsRBDs to DNA-RNA hybrids. Our study reveals the structural and molecular basis of protein-RNA interaction that gives rise to the observed substrate specificity of dsRNA binding proteins.
authors.affiliation: Department of Physics, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Lela
authors.initials: L
authors.lastname: Vuković
authors.forename: Hye Ran
authors.initials: HR
authors.lastname: Koh
authors.forename: Sua
authors.initials: S
authors.lastname: Myong
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000737:chemistry*; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D004247:DNA; D009692:Nucleic Acid Heteroduplexes; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D000099253:Trans-Activation Responsive RNA-Binding Protein