期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 26, 页码 10005-10010出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602317103
关键词
antiviral mechanism; autoinhibition; NMR; peptide activator; protein kinase
资金
- NCI NIH HHS [P01 CA062220, R01 CA068782, CA 68782, CA 62220] Funding Source: Medline
- NHLBI NIH HHS [HL 073311, P01 HL073311, R01 HL058758, HL 58758] Funding Source: Medline
The mammalian protein kinase PKR is a critical component of the innate immune response against virus infection. its cellular actions are mediated by modulating cell signaling and translational regulation. To be enzymatically active, latent PKR needs to be activated by binding to one of its activators, dsRNA or PACT protein. Although the structures of the N-terminal dsRNA-binding domain and the C-terminal kinase domain of PKR have been separately determined, the mode of activation of the enzyme remains unknown. To address this problem, we used biochemical, genetic, and NMR analyses to identify the PACT-binding motif (PBM) located in the kinase domain and demonstrated an intramolecular interaction between PBM and dsRNA-binding domain. This interaction is responsible for keeping PKR in an inactive conformation, because its disruption by point mutations of appropriate residues produced constitutively active PKR. Furthermore, a short decoy peptide, representing PBM, was able to activate PKR by interfering with the intramolecular interaction. These observations suggest a model for PKR activation upon binding of dsRNA or PACT.
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