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Literature summary for 3.6.5.3 extracted from

  • Bogorad, A.M.; Lin, K.Y.; Marintchev, A.
    Novel mechanisms of eIF2B action and regulation by eIF2alpha phosphorylation (2017), Nucleic Acids Res., 45, 11962-11979 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 3.6.5.3

Cloned(Commentary)

Cloned (Comment) Organism
gene EIF2B1, recombinant expression of C-terminally His6-tagged eIF2B subunit alpha in Escherichia coli strain Rosetta2(DE3) Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
phosphorylated eIF2 IF2alpha is phosphorylated at Ser51 by four kinases in what is collectively known as the integrated stress response (ISR). Phosphorylation of the eIF2alpha subunit in response to various cellular stresses converts eIF2-GDP into a competitive inhibitor of eIF2B, which triggers the integrated stress response (ISR) Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
GTP + H2O Homo sapiens
-
 GDP + phosphate
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens P05198 AND P20042 AND P41091 eIF2 subunits alpha, beta, and gamma
-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein IF2alpha is phosphorylated at Ser51 by four kinases in what is collectively known as the integrated stress response (ISR). Phosphorylation of Ser51 disrupts an intramolecular interaction between eIF2alpha-NTD and -CTD. This disruption exposes an eIF2B-binding surface on eIF2alpha-NTD that is otherwise obstructed by eIF2alpha-CTD. The intramolecular binding interface in eIF2alpha overlaps with the eIF2alpha binding surfaces for eIF2Bbeta, and possibly also eIF2Bdelta, in support of the hypothesis for an indirect effect of eIF2alpha phosphorylation on eIF2B-eIF2 binding. Phosphorylation destabilizes the eIF2alpha intramolecular interaction Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
GTP + H2O
-
 Homo sapiens GDP + phosphate
-
 ?
additional information substrate eIF2, phosphorylation of the eIF2alpha subunit in response to various cellular stresses converts substrate eIF2 into a competitive inhibitor of eIF2B, which triggers the integrated stress response (ISR) Homo sapiens ?
-
-

Synonyms

Synonyms Comment Organism
eIF2
-
 Homo sapiens

General Information

General Information Comment Organism
metabolism IF2alpha is phosphorylated at Ser51 by four kinases in what is collectively known as the integrated stress response (ISR) Homo sapiens
additional information modeling of the closed conformation of eIF2alpha, the model is generated from the structure of human eIF2alpha (PDB ID 1Q8K), based on the intramolecular contact interface mapped using CSPs from the NMR deletion analysis, comparing spectra of full-length eIF2alpha with those of its individual domains, eIF2alpha-NTD and -CTD, docking analysis and comparisons with the structure of Schizosaccharomyces pombe, intramolecular interaction in eIF2alpha. Further structure modeling of eIF2alpha binding in the eIF2Breg regulatory subcomplex pocket, eIF2B complex with eIF2-GTP-Met-tRNAi ternary complex, eIF2B complex with eIF2 in an extended conformation, and eIF2B complex with eIF2 in closed conformation. eIF2alpha-NTD interactions with the eIF2Breg pocket play a role in catalysis, and not just in eIF2B inhibition by phosphorylated eIF2-GDP (eIF2(alpha-P)-GDP). The primary mechanism responsible for the increased affinity of eIF2B for eIF2(alpha-P)-GDP over unphosphorylated eIF2-GDP is the direct effect of phosphorylation on the affinity of the eIF2x02 phosphorylation loop (P-loop) for a corresponding surface on eIF2B. eIF2Balpha and eIF2Bbeta bind to adjacent surfaces on eIF2-N-terminal domain (NTD), and eIF2Balpha, eIF2Bbeta, and eIF2Breg show no significant preference for phosphomimetic over wild-type eIF2alpha-NTD, binding analysis, overview Homo sapiens
physiological function eukaryotic translation initiation factor 2 (eIF2) is a heterotrimeric GTPase (cf. EC 3.6.5.1), which plays a critical role in protein synthesis regulation. eIF2-GTP binds MettRNAi to form the eIF2-GTP-Met-tRNAi ternary complex (TC), which is recruited to the 40S ribosomal subunit. Following GTP hydrolysis, eIF2-GDP is recycled back to TC by its guanine nucleotide exchange factor (GEF), eIF2B (i.e. eIF-2B GDP-GTP exchange factor). Mechanisms of eIF2B action and its regulation by phosphorylation of the substrate eIF2, overview. eIF2 consists of alpha, beta, and gamma subunits, with eIF2gamma being the actual GTPase, and eIF2alpha and beta serving accessory functions. eIF2B is inhibited by phosphorylated eIF2, eIF2(alpha-P)-GDP. Modeling of the structural and thermodynamic basis of the eIF2B/eIF2 and eIF2B/eIF2(alpha-P) interactions and the mechanism of catalysis, and modelling of the structural mechanism of IF2B inhibition by eIF2(alpha-P)-GDP, detailed overview Homo sapiens