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

Uversky, Vladimir N

Glutamic acid as a part of the protein degradation targeting signals, PEST motifs. PEST sequences (i.e., sequences enriched in proline (P), glutamic acid (E), serine (S) and threonine (T)) are known to serve as specific degradation signals. [159] [160] [161] [162] These degradation signals define cellular instability of many proteins and direct them either to the ubiquitin-proteasome degradation or to the calpain cleavage. 161, 162 This controlled protein degradation is important for activation and deactivation of regulatory proteins involved in signaling pathways that control cell growth, differentiation, stress responses and physiological cell death. [159] [160] [161] [162] PEST-containing sequences were shown to be solvent exposed and conformationally flexible, which preclude them from been resolved in X-ray structures. 159 Based on the comprehensive bioinformatics analysis of experimentally characterized disordered and globular regions and of PDB chains containing PEST regions, it has been concluded that the PEST motif is most frequently located within IDPRs. 161 Furthermore, analysis of the prolinerich motif Pro-X-Pro-X-Pro in PEST sequences revealed that these sequences contain glutamic acids much more often than aspartic acids. 161 In addition to this Pro-X-Pro-X-Pro motif, many PEST sequences are highly enriched in negatively charged residues and are characterized by a very specific distribution of negative charged patterns. 161 Glutamic acids in entropic bristle domains. The entropic bristle domain (EBD) concept was proposed to describe a characteristic behavior of some highly mobile protein regions. The several metals of the transition and main groups (Ib-Va, Z = 29−83) of the periodic table of elements. Phytochelatins are synthesized by a constitutive enzyme, γ-glutamylcysteine dipeptidyl transpeptidase, that uses glutathione (GSH) as a substrate and catalyzes the following reaction: γ-Glu-Cys-Gly + (γ-Glu-Cys) n − Gly→(γ-Glu-Cys) n+1 − Gly + Gly. 183 Fertilization promoting peptide. Another important glutamaterich peptide is fertilization promoting peptide (FPP; pGlu-Glu-ProNH2), which is produced by the prostate gland and secreted into seminal plasma. 184 FPP was shown to stimulate capacitation, which is the penultimate step in the maturation of mammalian spermatozoa required to render them competent to fertilize an oocyte. Furthermore, although FPP inhibits spontaneous loss of acrosome (an organelle that develops over the anterior half of the head in the spermatozoa), cells retain high fertility in vitro. 184 GALA peptide. Recently, a synthetic 30 amino acid-long GALA peptide with a glutamic acid-alanine-leucine-alanine (EALA) repeat was designed to analyze how viral fusion protein sequences interact with membranes. 185 This GALA peptide was long enough to span a bilayer when in the α-helical state, and the EALA repeat was adjusted so that the peptide would have a hydrophobic face of sufficient hydrophobicity to interact with the bilayer when the peptide was in an α-helix. Glu residues were used in GALA as a pH-responsive elements. 185 When the pH is reduced from 7.0 to 5.0, GALA converts from a water soluble random coil conformation to an amphipathic α-helix that binds to bilayer membranes. Functional analysis revealed that GALA promoted fusion between small unilamellar vesicles and was able to form a transmembrane pore comprised of ~10 GALA α-helical monomers that were oriented perpendicularly to the plane of the membran