title: Structure of the double-stranded RNA-binding domain of the protein kinase PKR reveals the molecular basis of its dsRNA-mediated activation.
abstract: Protein kinase PKR is an interferon-induced enzyme that plays a key role in the control of viral infections and cellular homeostasis. Compared with other known kinases, PKR is activated by a distinct mechanism that involves double-stranded RNA (dsRNA) binding in its N-terminal region in an RNA sequence-independent fashion. We report here the solution structure of the 20 kDa dsRNA-binding domain (dsRBD) of human PKR, which provides the first three-dimensional insight into the mechanism of its dsRNA-mediated activation. The structure of dsRBD exhibits a dumb-bell shape comprising two tandem linked dsRNA-binding motifs (dsRBMs) both with an alpha-beta-beta-beta-alpha fold. The structure, combined with previous mutational and biochemical data, reveals a highly conserved RNA-binding site on each dsRBM and suggests a novel mode of protein-RNA recognition. The central linker is highly flexible, which may enable the two dsRBMs to wrap around the RNA duplex for cooperative and high-affinity binding, leading to the overall change of PKR conformation and its activation.
authors.affiliation: Structural Biology Program, 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: B W
authors.initials: BW
authors.lastname: Carpick
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
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; D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D012330:RNA, Double-Stranded / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D019892:eIF-2 Kinase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase