The Integrated Stress Response is a critical eukaryotic signaling pathway that maintains cellular proteostasis. During amino acid scarcity, the yeast kinase Gcn2 (GCN2 in humans) and its activators Gcn1/Gcn20 phosphorylate eIF2 to reprogram translation, but how GCN2 senses nutrient stress in mammals is not known. Ribosome collisions serve as a major physiological trigger. Here we report a cryo-EM structure of human GCN1 bound to collided di-ribosomes. GCN1 specifically recognizes and rigidifies the flexible interface of the collided di-ribosome. Binding is mediated by contacts with both ribosomal P-stalks and a conserved segment that "pinches" the beak of the 40S subunit of the trailing ribosome. Functional assays confirm that multivalent Gcn1 contacts with collided ribosomes are essential for full Gcn2 activation in stressed yeast cells. Using nanobody-based proteomics in cells deprived of prolyl-tRNA, we identify ABCF3 as the primary mammalian ortholog of yeast Gcn20 recruited to ribosomes during amino acid starvation.
Chandrasekaran, V., Gupta, R., Angani, M. T., Haddad, T. F. M., Tate, C. G., Ramakrishnan, V., Hinnebusch, A. G.
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