title: A dynamically tuned double-stranded RNA binding mechanism for the activation of antiviral kinase PKR.
abstract: A key step in the activation of interferon-inducible antiviral kinase PKR involves differential binding of viral double-stranded RNA (dsRNA) to its two structurally similar N-terminal dsRNA binding motifs, dsRBM1 and dsRBM2. We show here, using NMR spectroscopy, that dsRBM1 with higher RNA binding activity exhibits significant motional flexibility on a millisecond timescale as compared with dsRBM2 with lower RNA binding activity. We further show that dsRBM2, but not dsRBM1, specifically interacts with the C-terminal kinase domain. These results suggest a dynamically tuned dsRNA binding mechanism for PKR activation, where motionally more flexible dsRBM1 anchors to dsRNA, thereby inducing a cooperative RNA binding for dsRBM2 to expose the kinase domain.
authors.affiliation: Structural Biology Program and Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nanduri
authors.forename: F
authors.initials: F
authors.lastname: Rahman
authors.forename: B R
authors.initials: BR
authors.lastname: Williams
authors.forename: J
authors.initials: J
authors.lastname: Qin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009038:Motion; D009587:Nitrogen Isotopes; D018583:Pliability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009587:Nitrogen Isotopes; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D019892:eIF-2 Kinase