EIF2S1
Description
The EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is a protein-coding gene located on chromosome 14.
Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the EIF2S1 gene. The protein encoded by this gene is the alpha (α) subunit of the translation initiation factor eIF2 protein complex which catalyzes an early regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA (Met-tRNAiMet) to 40S ribosomal subunits. Binding occurs as a ternary complex of methionyl-tRNA, eIF2, and GTP. eIF2 is composed of 3 nonidentical subunits, alpha (α, 36 kD, this article), beta (β, 38 kD), and gamma (γ, 52 kD). The rate of formation of the ternary complex is modulated by the phosphorylation state of eIF2α. Phosphorylation of eIF2α by EIF-2 kinases plays a key role in regulating the integrated stress response. After reperfusion following brain ischemia, there is inhibition of neuron protein synthesis due to phosphorylation of eIF2α. There is colocalization between phosphorylated eIF2α and cytosolic cytochrome c, which is released from mitochondria in apoptosis. Phosphorylated Eif2-alpha appeared before cytochrome c release, suggesting that phosphorylation of eIF2α triggers cytochrome c release during apoptotic cell death. Mice heterozygous for the S51A mutation become obese and diabetic on a high-fat diet. Glucose intolerance resulted from reduced insulin secretion, defective transport of proinsulin, and a reduced number of insulin granules in beta cells.
EIF2S1 is a component of the eIF2 complex, which plays a crucial role in the early stages of protein synthesis. It forms a ternary complex with GTP and initiator tRNA, facilitating the binding of this complex to a 40S ribosomal subunit. This leads to the formation of a 43S pre-initiation complex (43S PIC). Subsequent mRNA binding results in the formation of the 80S initiation complex. This process involves the hydrolysis of GTP bound to eIF2 and the release of an eIF2-GDP binary complex. For eIF2 to catalyze another round of initiation, the bound GDP must be exchanged with GTP through a reaction catalyzed by eIF2B. EIF2S1 is a key component of the integrated stress response (ISR), essential for adapting to various stresses. Phosphorylation by metabolic-stress sensing protein kinases (EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK, and EIF2AK4/GCN2) in response to stress converts EIF2S1 into a global protein synthesis inhibitor. This inhibits cap-dependent translation while promoting the translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1. This allows ATF4- and QRICH1-mediated reprogramming.
EIF2S1 is also known as EIF-2, EIF-2A, EIF-2alpha, EIF2, EIF2A.
Associated Diseases
- hyperinsulinism due to INSR deficiency
- exercise-induced hyperinsulinism
- hyperinsulinism due to glucokinase deficiency
- hypoinsulinemic hypoglycemia and body hemihypertrophy
- hyperinsulinism-hyperammonemia syndrome
- hyperinsulinemic hypoglycemia, familial, 2
- hyperinsulinemic hypoglycemia, familial, 1
- short stature due to partial GHR deficiency
- glycogen storage disorder due to hepatic glycogen synthase deficiency
- 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- hyperinsulinemic hypoglycemia, familial, 4
- severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency
- hyperinsulinism due to HNF1A deficiency
- autosomal recessive hyperinsulinism due to Kir6.2 deficiency
- islet cell adenomatosis
