2023年12月5日 · Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner.

2023年12月5日 · Herein, we identify a novel amino-acid-sensing mechanism of mTORC1 that utilizes uncharged transfer RNA (tRNA)-mediated general control nonderepressible 2 (GCN2) activation to augment the F-box only protein 22 (FBXO22) activity for mTOR ubiquitination and mTORC1 inhibition.

An activating mutation (GCN2c-E803V) that weakens PK-C-term association greatly enhanced tRNA binding by GCN2. These results provide strong evidence that tRNA stimulates the GCN2 kinase moiety by preventing an inhibitory interaction with the bipartite tRNA binding domain.

GCN2 stimulates translation of GCN4 mRNA in amino acid-starved cells by phosphorylating translation initiation factor 2. GCN2 is activated by binding of uncharged tRNA to a domain related to histidyl-tRNA synthetase (HisRS).

Activated GCN2 impacts many intracellular pathways in mammalian cells. Enhanced GCN2 activity can enhance methionyl-tRNA synthetase, eIF-2α and other molecules to redistribute protein translation via many pathways. The protein kinase GCN2 also regulates mRNA translation in mammals in an ATF4-independent manner . The translation of inducible ...

2024年6月6日 · The presence of a HisRS-like domain in GCN2, normally associated with tRNA aminoacylation, led to the hypothesis that eIF2α kinase activity is regulated by the direct binding of this domain to uncharged tRNA. Here we solved the structure of the HisRS-like domain in the context of full-length GCN2 by cryoEM.

2018年2月14日 · Different conditions can stimulate amino acid deprivation and increase levels of uncharged tRNA, which activate the amino acid sensor GCN2. This represents a checkpoint whereby cells...

2023年11月28日 · 近日，沈少明、陈国强、苏冰课题组合作，在国际著名期刊《细胞代谢》（Cell Metabolism）上在线发表了题为《The tRNA-GCN2-FBXO22 axis-mediated mTOR ubiquitination senses amino acid insufficiency》的研究论文，首次发现细胞内各种氨基酸浓度的改变可以统一地通过mTOR泛素化来被 ...

2015年2月19日 · The yeast Saccharomyces cerevisiae has a single eIF2α kinase, Gcn2, activated by uncharged tRNAs that accumulate in amino acid starved cells, which bind to a regulatory domain homologous to histidyl-tRNA synthetase (HisRS). Gcn2 also contains a C-terminal domain implicated in autoinhibition of Gcn2.

2000年3月3日 · An activating mutation (GCN2 c-E803V) that weakens PK–C-term association greatly enhanced tRNA binding by GCN2. These results provide strong evidence that tRNA stimulates the GCN2 kinase moiety by preventing an inhibitory interaction with the …