EEF1B2 (eukaryotic translation elongation factor 1 beta 2)

	Figure. 1. EEF1B2 gene and splicing variants/isoforms. The figure shows the locus on chromosome 2 of the EEF1B2 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)
Description	EEF1B2 (eukaryotic translation elongation factor 1 beta 2) was identified for the first time by Sanders and colleagues in 1991 (Sanders et al, 1991) and afterwards, its gene location was described by Pizzuti and colleagues in 1993 (Pizzuti et al, 1993). EEF1B2 is a protein-coding gene that starts at 206,159,594 nt and ends at 206,162,929 nt from pter. It has a length of 3,336 bp and the current reference sequence is NC_000002.12. It is proximal to SNORA41 (small nucleolar RNA, H/ACA box 41) gene, SNORD51 (small nucleolar RNA, C/D box 51) gene and NDUFS1 (NADH:ubiquinone oxidoreductase core subunit S1) gene. Near to the genomic sequence of EEF1B2 there is a strong promoter transcriptional element that is located at -0.2 kb.
Transcription	Three main alternative splicing transcript variants for EEF1B2 were detected although several others were reported. The three main transcript variants differ from each other only in the 5' UTR. In addition, it was speculated the presence of four protein isoforms, one main isoform of 225 amino acids and other three minor isoforms of 123 residues, 68 residues and 29 residues respectively. However, only the protein with the highest number of amino acids was detected. The main characteristics of the alternative splicing transcript variants are reported in Table.1. > Name Variant RefSeq (1) Transcript ID Exons Type Lenght (bp) Isoform Alias RefSeq (2) Lenght (aa) MW (kDa) pI EEF1B2-201  (EEF1B2-001) Var.2 NM_021121.3 ENST00000236957.9 7 protein coding 844 (854) - P24534  NP_066944.1 225 24.76 4.50 EEF1B2-202  (EEF1B2-201) Var.3 NM_001037663.1 ENST00000392221.5 7 protein coding 880 (900) - P24534  NP_001032752.1 225 24.76 4.50 EEF1B2-203  (EEF1B2-003) Var.1 NM_001959.4  ENST00000392222.7 6 protein coding 808 - P24534  NP_001950.1 225 24.76 4.50 EEF1B2-204  (EEF1B2-005) - - ENST00000415904.1 4 nonsense md 649 - - - 68 - - EEF1B2-205  (EEF1B2-007) - - ENST00000429769.5 8 nonsense md 912 - - - 68 - - EEF1B2-206 (EEF1B2-009) - - ENST00000435123.1  3 nonsense md 389 - - - 29 - - EEF1B2-207 (EEF1B2-004) - - ENST00000445505.5 5 protein coding 515 - - - 123 - - EEF1B2-208 (EEF1B2-010) - - ENST00000455150.1 6 nonsense md 670 - - - 68 - - EEF1B2-209  (EEF1B2-008) - - ENST00000460760.1 2 retained intron 1025 - - - - - - EEF1B2-210  (EEF1B2-006) - - ENST00000479587.1 3 retained intron 701 - - - - - - EEF1B2-211 (EEF1B2-002) - -  ENST00000482103.1 2 retained intron 587 - - - - - - Table.1 Alterative splicing variants and isoforms of EEF1B2.(reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; https://web.expasy.org/protparam/; https://www.uniprot.org)
Pseudogene	According to Entrez Gene, the analysis of the human genome revealed the presence of several pseudogenes for EEF1B2 (Table.2), which are perhaps related to recent retrotransposition events (Chambers et al, 2001). The alternative forms EEF1B3 and EEF1B4 previously designated for EEF1B2 (Pizzuti et al, 1993) have instead proved to be pseudogenes: i.e. EEF1B2P2 and EEF1B2P3 respectively. If these elements have any regulatory role in the expression of the respective gene as described for others (Hirotsune et al., 2003), is only speculation in the absence of experimental evidence. Currently, there is no evidence about the involvement of these pseudogenes in human cancers or in other diseases. Gene Gene  name Gene ID RefSeq Locus Location Start End Lenght (nt) Main diseases Reference EEF1B2P1 EEF1B2 pseudogene 1 1932 NC_000015.10 Chromosome 15 15q21.2 52505029 52505908 880 - - EEF1B2P2 EEF1B2 pseudogene 2 1934 NC_000005.10 Chromosome 5 5q13.1 68159175 68159977 803 - - EEF1B2P3 EEF1B2 pseudogene 3 644820 NC_000023.11 Chromosome X Xp22.11 24788347 24789110 764 - - EEF1B2P4 EEF1B2 pseudogene 4 100130631 NC_000012.12 Chromosome 12 12q23.3 106901238 106902398 1161 - - EEF1B2P5 EEF1B2 pseudogene 5 442227 NC_000006.12 Chromosome 6 6q12 63480050 63481926 1877 - - EEF1B2P6 EEF1B2 pseudogene 6 647030 NC_000007.14 Chromosome 7 7q32.3 131661900 131662665 766 - - EEF1B2P7 EEF1B2 pseudogene 7 100421756 NC_000002.12 Chromosome 2  2q37.1 232729478 232730276 799 - - EEF1B2P8 EEF1B2 pseudogene 8 100421774 NC_000003.12 Chromosome 3 3q26.31 175059315 175060110 796 - - Table.2 EEF1B2 pseudogenes (reworked from https://www.ncbi.nlm.nih.gov/gene/1933; https://www.targetvalidation.org; https://www.ncbi.nlm.nih.gov/geoprofiles/) [ (?) ] uncertain; [ - ] no reference

	Figure.2 eEF1B2 protein. Graphical representation of eEF1B2 protein with the evidence of the main verified post-translational modifications (reworked from Le Sourd et al., 2006; http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; http://bioinf.umbc.edu/dmdm/gene_prot_page.php; http://www.hprd.org/ptms?hprd_id=02804&isoform_id=02804_1&isoform_name=Isoform_1).
Description	The eukaryotic translation elongation factor 1 beta 2 (alias eEF1B2, eEF1β, eEF1Bα) is the smallest subunit of the macromolecular eukaryotic translation elongation factor-1 complex (alias eEF1, also called eEF1H)(Cao et al, 2014), a high-molecular-weight form made up of an aggregation of different protein subunits: EEF1A1 (alias eEF1α), EEF1B2, EEF1G (alias eEF1γ, heEF1γ, eEF1Bγ), EEF1D (alias eEF1δ, eEF1Bδ) and VARS2 (valyl t-RNA synthetase val-RS). eEF1H protein complex plays a central role in peptide elongation during eukaryotic protein biosynthesis, in particular for the delivery of aminoacyl-tRNAs to the ribosome mediated by the hydrolysis of GTP. In fact, during the translation elongation step, the inactive GDP-bound form of eEF1A (eEF1A-GDP) is converted to its active GTP-bound form (eEF1A-GTP) by eEF1BGD-complex through GTP hydrolysis. Thus eEF1BGD-complex acts as a guanine nucleotide exchange factor (GEF) for the regeneration of eEF1A-GTP for the next elongation cycle. The physiological role of eEF1B2 in the translation is fundamental to permit the conversion of the inactive form eEF1A-GDP into its corresponding active form eEF1A-GTP. In particular, eEF1B2 strictly collaborate with eEF1D and eEF1G in the conversion of eEF1A from its inactive GDP-bound form to its active GTP-bound form and so it covers a role as a guanine nucleotide exchange factor (GEF) for eEF1A (Le Sourd et al., 2006; Browne and Proud, 2002). It was shown that the nucleotide exchange reaction by eEF1B2 is inhibited by Mg2+ that binds on K205 residue. Only after the displacing of Mg2+ from its binding site eEF1B2 can function correctly (Pittmann et al, 2006). In prokaryotes, the homolog of eEF1B2 is known as EF-Ts, while in eukaryotes it is known only one functional protein form with the reference sequence NP_001950.1 by 225 residues. It is found in the eEF1H protein complex and it shows many domains: in the carboxyl half terminal there is an EF-1 guanine nucleotide exchange domain (EF1-GNE domain / GEF) while in the amino half terminal there is a region called GST-C-eEF1b-like domain (Glutathione S-transferase C-terminal-like domain)(see figure.2). The fold of the C-terminal domain of eEF1B2 is found very similar to that many ribosomal proteins, i.e. it shows two so-called split b-a-b motifs (Andersen et al, 2003). This region possesses nucleotide exchange activity and interacts with eEF1A (Le Sourd et al., 2006). The non-catalytic N-terminal domain of eEF1B2, that interacts with the N-terminal domain of eEF1G (Le Sourd et al., 2006; van Damme et al, 1991), has a regulatory role on the eEF1B2 itself because it can interfere with the guanine nucleotide exchange activity located on the C-terminal domain. In fact, the non-catalytic N-terminal domain of eEF1B2 brings to the reduction in the overall rate of the guanine nucleotide exchange reaction mediated by eEF1B2. It is only thanks to the bond of eEF1B2 with eEF1G that this inhibitory effect is abolished (Trosiuk et al, 2016). EEF1B2 interacts primarily with eEF1A1/ EEF1A2 and eEF1G but also with valyl -tRNA synthetase (Val-RS)(Le Sourd et al., 2006; Bec et al., 1994). Seems that there are no direct interactions between eEF1B2 and eEF1D (Cao et al, 2014; Sheu and Traugh, 1997), although different interactional models were proposed (Le Sourd et al., 2006; Jiang et al.,2005; Sheu and Traugh, 1999; Minella et al., 1998). In addition, eEF1B2 interact with translationally controlled tumor protein (TCTP) but the nature of this interaction is still poorly understood (Wu et al, 2015). Post-translational modifications. Some post-translational modifications are observed, such as phosphorylation and acetylation (https://www.ncbi.nlm.nih.gov). Phosphorylations of eEF1B2 are made by some protein kinases, including casein kinase 2 (CK2) (Browne and Proud, 2002).
	Figure 3. The translation elongation mechanism. The active form of eukaryotic translation elongation factor 1 alpha (eEF1A) in complex with GTP delivers an aminoacylated tRNA to the A site of the ribosome. Following the proper codon-anticodon recognition the GTP is hydrolyzed and the inactive eEF1A-GDP is released from the ribosome and then it is bound by eEF1B2GD complex forming the macromolecular protein aggregate eEF1H. eEF1H is formed previously by the binding of three subunits: eEF1B2, eEF1G and eEF1D. This complex promotes the exchange between GDP and GTP to regenerate active form of eEF1A (reworked from Li et al., 2013; Ejiri, 2002; Riis et al, 1990; https://reactome.org)
Expression	eEF1B2 is expressed widely in human tissues (https://www.genecards.org) although its expression is not uniform in either tissues or cell lines (Cao et al, 2014).
Localisation	eEF1B2 is located mostly in the cytoplasm but it was also found in the nucleus (https://www.genecards.org/cgi-bin/carddisp.pl?gene=EEF1B2). It shows a perinuclear distribution (Sanders et al, 1996) and it is found on the endoplasmic reticulum (Cho et al, 2003; Sanders et al, 1996).
Function	eEF1B2 plays a fundamental role in the cell, in particular in the translation elongation step. In fact, eEF1B2 shows canonical functions and multiple non-canonical roles (moonlighting roles) inside the cell. Canonical function: eEF1B2 binds to eEF1D and eEF1G in the eEF1B2DG macromolecular complex and contributes to catalyze the exchange of GDP/GTP for eEF1A during the translation elongation cycle. It was shown that eEF1B2 has the ability to disrupt eEF1A-induced actin organization and so engage eEF1A for protein synthesis (Pittman et al, 2009). Non-canonical roles: eEF1B2 seems to have other functions inside the cell besides its involvement in translation. Together with eEF1D and eEF1G, it controls the translation fidelity (Le Sourd et al, 2006) and in response to stressors such as heat shock, oxidative stress, and toxins, it mediates the inhibition of protein synthesis. In addition, it seems to have interaction with the cytoskeleton (Khudhair et al., 2014), but the effect of eEF1B2 on actin filaments is still poorly understood (Sasikumar et al, 2012).
Homology	eEF1B2 is highly conserved and its homology between the species is reported in Table.3 Organism Species Symbol  DNA Identity (%) PROT Identity (%) Human H.sapiens EEF1B2 100 100 Chimpanzee P.troglodytes EEF1B2 99.9 100 Macaco M.mulatta EEF1B2 97.6 99.6 Wolf C.lupus EEF1B2 93.0 98.2 Cattle B.taurus EEF1B2 91.1 97.8 Mouse  M.musculus Eef1b2 89.2 95.6 Rat R.norvegicus Eef1b2 89.2 94.7 Chicken G.gallus EEF1B2 82.0 93.3 Xenopus tropicalis X.tropicalis eef1b2 78.1 85.3 Zebrafish  D.rerio eef1b2 73.8 82.6 Fruit fly D.melanogaster Ef1beta 58.7 58.8 Mosquito (Anopheles) A.gambiae AgaP_AGAP010612 60.2 62.0  Caenorhabditis  C.elegans  eef-1B.1 55.1 53.1 Table.3 EEF1B2 homology (reworked from htpps://www.ncbi.nlm.nih.gov/homologene)

Note	A great number of mutations in the genomic sequence and in the amino acid sequence for EEF1B2 were discovered in cancer cells that are obviously genetically more unstable respect normal ones. The genomic alterations observed include the formation of novel fusion genes. However, there are no sufficient experimental data yet to understand the repercussions on cellular behaviour and so the implications in cancer of these alterations.
	Figure 4. Circos plot for fusion events involving eEF1B2. The picture summarizes all fusion events concerning eEF1B2 and its fusion partners (from https://fusionhub.persistent.co.in/search_genewise.html).

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