The alphabet of intrinsic disorder: II. Various roles of glutamic acid in ordered and intrinsically disordered proteins

Uversky, Vladimir N

eIF5. Eukaryotic translation initiation factor 5 (eIF5) is a monomeric protein of about 49 kDa that functions as a GTPaseactivating protein (GAP) in translation initiation. eIF5 is involved in initiation of protein synthesis in eukaryotic cells, where, after binding to the 40S initiation complex (40S-eIF3-mRNA-Met-tRNA f -eIF2-GTP) at the AUG codon of an mRNA, it promotes GTP hydrolysis. This initiates a cascade of events that starts from the release of bound initiation factors from the 40S subunit and ends with the joining of the 60S ribosomal subunit to the 40S complex to form the functional 80S initiation complex (80S-mRNA-Met-tRNA f ). 193 Although eIF5 binds GTP and is able to promote GTP hydrolysis reaction, it does not hydrolyze GTP by itself acting as a typical GTPase-activating protein (GAP). In fact, eIF5 forms a complex with eIF2 via its glutamic acidrich C-terminal region that binds to the lysine-rich N-terminal region of the β-subunit of eIF2 thus activating the GTPase activity of eIF2. 193 In human eIF5, the 3D structure is known for the N-terminal nucleotide binding domain (residues 1-150, PDB ID: 2E9H) and for the W2 domain (residues 232-431, PDB ID: 2IU1). The linker region connecting these two domains is highly disordered and contains one of the functionally important glutamic acid-rich regions (residues [196] [197] [198] [199] [200] [201] [202] . Overall, there are 11.4% glutamic acid residues in the 431 residues-long amino acid sequence of human eIF5.