Structure of the kinase domain of human RNA-dependent protein kinase with K296R mutation reveals a face-to-face dimer

Li, FengZhi; Li, Siwei; Wang, Zheng; Shen, Yuequan; Zhang, TongCun; Yang, Xue

doi:10.1007/s11434-012-5461-z

Cited by 9 publications

(17 citation statements)

References 23 publications

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“…The association of RBM2 on the alternative face, at the C-lobe of the kinase domain, could also repress dimerization by impeding the formation of transitional states of PKR. Although PKR protomers associate in a back-to-back orientation in the active enzyme22, Li et al 51. identified that introducing a phosphor-mimetic mutated at the essential catalytic residue (T446D) in the kinase-dead molecule enabled them to isolate a dimeric molecule that adopted an alternative face-to-face orientation.…”

Section: Discussionmentioning

confidence: 99%

Auto-phosphorylation Represses Protein Kinase R Activity

Wang

Weerd

Willard

et al. 2017

Sci Rep

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The central role of protein kinases in controlling disease processes has spurred efforts to develop pharmaceutical regulators of their activity. A rational strategy to achieve this end is to determine intrinsic auto-regulatory processes, then selectively target these different states of kinases to repress their activation. Here we investigate auto-regulation of the innate immune effector protein kinase R, which phosphorylates the eukaryotic initiation factor 2α to inhibit global protein translation. We demonstrate that protein kinase R activity is controlled by auto-inhibition via an intra-molecular interaction. Part of this mechanism of control had previously been reported, but was then controverted. We account for the discrepancy and extend our understanding of the auto-inhibitory mechanism by identifying that auto-inhibition is paradoxically instigated by incipient auto-phosphorylation. Phosphor-residues at the amino-terminus instigate an intra-molecular interaction that enlists both of the N-terminal RNA-binding motifs of the protein with separate surfaces of the C-terminal kinase domain, to co-operatively inhibit kinase activation. These findings identify an innovative mechanism to control kinase activity, providing insight for strategies to better regulate kinase activity.

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Section: Discussionmentioning

confidence: 99%

Auto-phosphorylation Represses Protein Kinase R Activity

Wang

Weerd

Willard

et al. 2017

Sci Rep

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“…Although the structure of inactive, monomeric PKR is not available, the structure of the active, dimeric PKR kinase domain suggested that the dimerization of the N-terminal lobe of the kinase domain likely induces conformational changes in the αC helix and the activation segments in a manner similar to other wellcharacterized kinases (69, 80) ( Figure 2b). The structure also showed how the autophosphorylation of Thr446 in the activation segment further helps stabilize the active site conformation (80,81) (Figure 2b). Altogether, these observations support the model where dsRNA binding brings two or more PKR molecules in close proximity to allow dimerization of the kinase domain ( Figure 2b).…”

Section: Protein Kinase Rmentioning

confidence: 95%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

293

286

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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“…The X-ray structure of a kinase-dead K296R PKR mutant was essentially identical to the wild-type activated structure, except for the disordered activation and P + 1 loops due to unphosphorylated T446 ( Fig. 1D; Li et al 2012). Since high concentrations of PKR can induce dimerization and activation (Lemaire et al 2005), this mutant structure likely represents an activated state prior to autophosphorylation instead of an authentic inactive state.…”

Section: Effector Kinase Domainmentioning

confidence: 83%

The search for a PKR code—differential regulation of protein kinase R activity by diverse RNA and protein regulators

Bou‐Nader

Gordon

Henderson

et al. 2019

RNA

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The interferon-inducible protein kinase R (PKR) is a key component of host innate immunity that restricts viral replication and propagation. As one of the four eIF2α kinases that sense diverse stresses and direct the integrated stress response (ISR) crucial for cell survival and proliferation, PKR's versatile roles extend well beyond antiviral defense. Targeted by numerous host and viral regulators made of RNA and proteins, PKR is subject to multiple layers of endogenous control and external manipulation, driving its rapid evolution. These versatile regulators include not only the canonical doublestranded RNA (dsRNA) that activates the kinase activity of PKR, but also highly structured viral, host, and artificial RNAs that exert a full spectrum of effects. In this review, we discuss our deepening understanding of the allosteric mechanism that connects the regulatory and effector domains of PKR, with an emphasis on diverse structured RNA regulators in comparison to their protein counterparts. Through this analysis, we conclude that much of the mechanistic details that underlie this RNA-regulated kinase await structural and functional elucidation, upon which we can then describe a "PKR code," a set of structural and chemical features of RNA that are both descriptive and predictive for their effects on PKR.

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Structure of the kinase domain of human RNA-dependent protein kinase with K296R mutation reveals a face-to-face dimer

Cited by 9 publications

References 23 publications

Auto-phosphorylation Represses Protein Kinase R Activity

Auto-phosphorylation Represses Protein Kinase R Activity

Double-Stranded RNA Sensors and Modulators in Innate Immunity

The search for a PKR code—differential regulation of protein kinase R activity by diverse RNA and protein regulators

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