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Fig. 3 | Experimental Hematology & Oncology

Fig. 3

From: Targeting the integrated stress response in hematologic malignancies

Fig. 3

Activation mechanisms of the eIF2α kinases. Diverse stimuli cause the eIF2α kinases to undergo activation via autophosphorylation (indicated by orange shading of kinase domains). A In the absence of ER stress GRP78 binds to the luminal domain (purple) of PERK preventing it from dimerizing and undergoing activation via trans-autophosphorylation (P). The presence of misfolded proteins titrates GRP78 from PERK which facilitates dimerization converting PERK into an active kinase (activation status shown in orange). Misfolded proteins can also interact directly with the luminal domain to stimulate PERK activation. B PKR is canonically activated by interaction between the double stranded RNA binding domains (dsRBD, shown in green) and dsRNA. PKR can also be activated by direct interaction with the PKR activating protein PACT (shown in pink). The lipid ceramide (purple) can also directly interact with PKR to stimulate its activity. C During nutrient availability, GCN2 is an inactive homodimer due to inhibitory interactions between the C-terminal domain (CTD), histidyl-tRNA synthetase (HisRS) domain and kinase domains. Amino acid depletion causes an increase in levels of uncharged tRNA which displace the CTD causing rearrangement of the regulatory regions to facilitate activation of the enzyme. D Heme (H) binds to the HRI homodimer to stabilize it in an inactive conformation. Depletion of heme allows HRI to adopt an active configuration. Created with BioRender.com

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