EIF2B3 gene consists of 12 exons and 11 introns. The gene maps to 1p34.1 and is 136,201 bp long (NCBI Reference Sequence: NC_000001.11: 44850522-44986722). Highlighted in orange is the protein coding sequence from exons 2-12 (Figure 2).

EIF2B3 gene is 136,201 bp long and is on the minus strand. This gene has 12 exons.

EIF2B3 produces 3 coding mRNA transcripts (1900 bp, 1607 bp, and 1923 bp). The first transcript variant is the longest one with 12 exons. The difference between the first and the third variant is the absence of the 11th exon in the third variant resulting in a shorter transcript. The second variant lacks the last two coding exons of the first variant and is the shortest transcript variant among the three isoforms (NCBI, 2020).

The gene coding EIF2B3 encodes a 452 amino acid protein. This protein is a member of the subunits of initiation factor eIF2B. It has an estimated molecular weight of 50,240 kDa (Wortham et al., 2014).

EIF2B3 protein catalyzes the exchange of GDP for GTP bound to the eukaryotic initiation factor 2. Through its highly conserved NT domain, EIF2B3 is an essential component of a decameric complex with other EIF2B subunits required for translational initiation and regulation (Pavitt, 2005). Additionally, AT domain containing hexad repeats of isoleucyl residues (also termed as I-patch region) plays a key role in the interaction of the catalytic subcomplex of the EIF2B complex with other domains (Wang et al., 2012).

EIF2B3 protein is detected in almost all human tissues. The expression is mostly cytoplasmic in human tissues (The Human Protein Atlas, 2020). The protein expression for EIF2B3 is highest in pancreas, thyroid gland, and breast tissue (Samaras et al., 2019)

EIF2B3 protein localizes to the cytosol with the other proteins of the EIF2B complex (Hodgson et al., 2019).

EIF2B3, is one of the important subunits of the decameric complex of EIF2B with guanine nucleotide exchange factor (GEF) activity. During the initiation of translation, eukaryotic initiation factor-2, a heterotrimeric GTPase, forms a ternary complex with Met-tRNAi which is delivered to 40S ribosomal subunit (Pavitt, 2005). After the recognition of AUG codon by Met-tRNAi at the P site, eIF2-GTP is hydrolyzed resulting in the release of inactive eIF2-GDP, which aids 40S and 60S ribosomal subunit assembly (Pavitt, 2005). In this inactive state of eIF2, the initiation of new rounds of translation is not possible unless there is a switch from GTP to GDP (Mohammad-Qureshi, Jennings, & Pavitt, 2008). Hence, eIF2B activating the eIF2 by exchanging GDP for GTP with its GEF activity is a key factor for translation (Mohammad-Qureshi et al., 2008).
EIF2B has five subunits (α - ε), which form the regulatory and the catalytic sub-complexes. EIF2Bγ (EIF2B3) together with EIF2B5 (EIF2Bε) form the catalytic sub-complexes (EIF2Bcat), while EIF2B1 (EIF2Bα), EIF2B2 (EIF2Bβ), and EIF2B4 (EIF2Bδ) subunits form the regulatory sub-complexes (EIF2Breg) (Hinnebusch & Yang, 1996; Kashiwagi et al., 2016). The catalytic sub-complex is responsible for the GEF activity of the complex. Some studies suggest that eIF2Bε itself is enough for GEF activity in vitro; however, activity may be very low without EIF2B3 (Gomez, Mohammad, & Pavitt, 2002). On the contrary, another study suggests that γ and ε subunits together have the GEF function; indeed, the pyrophosphorylase-like (PL) domain of γ subunit is the main responsible part for GTP binding (Gordiyenko et al., 2014).
EIF2B3 was reported to be a cofactor for hepatitis C virus (HCV) IRES-mediated protein translation (Kruger et al., 2000).
The expression level, availability and activity eukaryotic initiation factors are usually regulated by key signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) pathways. Deregulation of these pathways may have significant effect on translation initiation through initiation factors (Hao et al., 2020).

EIF2B3 gene has high homology across species, including chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, S.pombe, M.oryzae, N.crassa, A.thaliana, rice, and frog (NCBI HomoloGene, 2020). So far, 317 orthologous genes to human EIF2B3 gene have been reported (NCBI, 2020).

According to COSMIC database, 683 samples out of 37,420 unique samples from cancer patients have EIF2B3 mutations. There are 143 unique substitution mutations in 860 cancer patients for EIF2B3 gene. 14% of all the reported mutations are missense mutations (COSMIC database, 2018). Mutation burden is generally low for different cancer types, but the alteration frequency is the highest for endometrial carcinoma with 5.12% in 586 cases (cBioPortal database) (Cerami et al., 2012; Gao et al., 2013).
EIF2B3 mutations may also be related to vanishing white matter disease and ovarian failure (La Piana et al., 2012).