eIF2GDP

eIF2GDP refers to the GDP-bound form of the eukaryotic initiation factor 2 (eIF2), a heterotrimeric GTPase essential for the initiation of protein synthesis in eukaryotic cells. The eIF2 complex comprises alpha, beta, and gamma subunits, with the gamma subunit binding and hydrolyzing guanine nucleotides (GTP or GDP).

In its active state, eIF2 binds GTP and initiator methionyl-tRNA (Met-tRNAi) to form a ternary complex that delivers Met-tRNAi to the ribosome as part of the translation initiation process. After start codon recognition during initiation, GTP is hydrolyzed to GDP, and the eIF2 complex can no longer participate in further rounds of initiation until it is recharged. The GDP-bound form, eIF2GDP, is thus considered inactive in driving initiation until it is regenerated to the GTP-bound form.

Recycling of eIF2GDP to eIF2GTP is mediated by the guanine nucleotide exchange factor eIF2B, which catalyzes the exchange of GDP for GTP on the gamma subunit. This exchange is a key regulatory step in translation initiation and ensures a continuous supply of active eIF2GTP for new rounds of initiation.

Regulation of this cycle is a major control point in cellular stress responses. Phosphorylation of the eIF2α subunit (Ser51 in humans) by stress-activated kinases converts eIF2 into a competitive inhibitor of eIF2B, reducing GDP-GTP exchange and lowering global translation while allowing selective translation of certain mRNAs, such as ATF4. Thus, eIF2GDP is a central intermediate in both the normal control and stress-related regulation of protein synthesis.