EIF2B1 UniProt Q14232

3 alternative isoforms · canonical 305 aa · cytosol

EIF2B1 encodes eIF2Bα, the regulatory subunit of the eIF2B guanine-nucleotide exchange complex that controls the rate of translation initiation by recycling eIF2·GDP to eIF2·GTP [PMID:9139680, PMID:11323413]. eIF2Bα is dispensable for basal catalytic exchange — a four-subunit complex lacking it retains high GEF (GDP-dissociation) activity — but it is essential to confer the inhibition of eIF2B that occurs when the substrate eIF2α is phosphorylated under stress, with recombinant eIF2Bα restoring this regulation in vitro [PMID:9139680, PMID:11323413]. This regulatory function is evolutionarily conserved, and loss of eIF2Bα or a T41A point mutant neutralizes the translational shutdown triggered by eIF2α phosphorylation in mammalian cells, rendering them susceptible to viral infection [PMID:11060303, PMID:21795329]. Structurally, mammalian eIF2B is a decamer — a dimer of (βγδε) tetramers bridged by two copies of eIF2Bα — and this decameric assembly binds eIF2 more avidly and supports higher activity than the tetramer alone [PMID:24532666, PMID:24811713]. Cryo-EM of the eIF2B–phospho-eIF2 complex shows that eIF2α-D1 bearing phospho-Ser51 inserts between the helix-bundle domains of eIF2Bα and eIF2Bδ, establishing eIF2Bα as the primary docking surface for phospho-eIF2α; viral antagonists such as the Sandfly Fever Sicilian virus NSs protein competitively occupy this same eIF2Bα site to rescue GEF activity [PMID:31201334, PMID:34876554]. Beyond stress sensing, eIF2Bα carries an ancestral catalytic pocket homologous to sugar-phosphate metabolic enzymes that binds sugar phosphates to allosterically promote holoenzyme assembly and stimulate GEF activity, linking nutrient and glycolytic status to protein synthesis [PMID:26384431, PMID:34103529]. Mutations in EIF2B1 cause vanishing white matter disease — typically by reducing eIF2Bα levels and complex stability or by disrupting regulation by phospho-eIF2α [PMID:14993275, PMID:26285592] — and de novo missense mutations clustering on one surface cause permanent neonatal/early-onset diabetes with transient hepatic dysfunction [PMID:31882561]. The decameric eIF2Bα-dependent complex is also required for oncogenic translation in APC-deficient colorectal cancer, defining a therapeutic vulnerability [PMID:40016419].