EIF2AK4 (GCN2) binds tRNA

The histidyl-tRNA synthetase-like domain of EIF2AK4 (GCN2) binds uncharged tRNA, resulting in activation of the protein kinase domain of EIF2AK4 (Inglis et al. 2019 and inferred from yeast homologs and mouse homologs). In the absence of tRNA, EIF2AK4 appears to exist in an equilibrium between antiparallel and parallel dimers. Upon binding tRNA, the parallel dimer is stabilized and the C-terminal domain shifts away from the protein kinase domain, resulting in activation of the kinase activity of EIF2AK4 (inferred from GCN2, the yeast homolog).<br>EIF2AK4 interacts with GCN1 and the P-stalk of ribosomes (Inglis et al. 2019), though the interaction between mammalian EIF2AK4 and ribosomes is not as stable as the interaction between yeast GCN2 and ribosomes (inferred from yeast homologs and mouse homologs). By such transient interactions, a population of EIF2AK4 may sample a larger population of ribosomes for uncharged tRNAs. The interaction between EIF2AK4 and GCN1 is required for efficient phosphorylation of EIF2S1 by EIF2AK4 and GCN1 may act to transfer uncharged tRNAs from the A site of the ribosome to EIF2AK4 (inferred from yeast homologs and mouse homologs).

EIF2AK4（GCN2）的组氨酸-tRNA合成酶样结构域与未电荷的tRNA结合，导致EIF2AK4（Inglis等，2019年）蛋白激酶结构域的激活（据酵母同源物和小鼠同源物推断）。在缺乏tRNA的情况下，EIF2AK4似乎处于反平行和并行二聚体的平衡状态。当结合tRNA时，并行二聚体得以稳定，C端结构域远离蛋白激酶结构域，从而激活EIF2AK4的激酶活性（据GCN2，酵母同源物推断）。EIF2AK4与GCN1和核糖体的P臂相互作用（Inglis等，2019年），尽管哺乳动物EIF2AK4与核糖体的相互作用不如酵母GCN2与核糖体的相互作用稳定（据酵母同源物和小鼠同源物推断）。通过此类瞬时相互作用，EIF2AK4的一个群体可能采样更大的核糖体群体以获取未电荷的tRNA。EIF2AK4与GCN1的相互作用对于EIF2AK4对EIF2S1的有效磷酸化至关重要，GCN1可能作用于将未电荷的tRNA从核糖体的A位点转移到EIF2AK4（据酵母同源物和小鼠同源物推断）。