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

Uversky, Vladimir N

cle trauma or neuromuscular disease. It also possesses hyaluronidase activity, serine protease activity, pro-inflammatory and anti-inflammatory activity and is involved in the suppression of lymphocyte necrosis, inhibition of cellular adhesion, and binding of divalent metal ions. Finally, hemopexin possesses two highly exposed Arg-Gly-Glu sequences that may promote interaction with cell surfaces. 112 Glutamic acid plays an important role in defining the retinal binding site geometry of rhodopsin, which is the photoreceptor in vertebrate rod cells responsible for vision at low light intensities. 11-cis-retinal is the photoreactive chromophore located in the interior of the protein where it is covalently attached to a lysine side chain through a protonated Schiff base (PSB) linkage. 113 Based on the 13 C-NMR chemical shift data, it was concluded that Glu113 of rhodopsin is involved in charge interactions with the retinal PSB, which are crucial for maintaining rhodopsin in the inactive state in the dark and whose breaking leads to the protein activation. 113 A centrally located glutamic acid residue in position 6 of transmembrane segment VII of the main ligand-binding crevice of the chemokine 7TM receptors (GluVII:06) is crucial for recognition and binding of small molecule non-peptide ligands that contain one or two centrally located, positively charged nitrogen atoms and are characterized by relatively similar elongated overall structure with terminal aromatic moieties. 114 Furthermore, since this GluVII:06 is crucial for the binding and hence the function of a number of non-peptide ligands in several chemokine receptors, such as the CCR1, CCR2 and CCR5 receptors, it serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule ligands. 114 Glutamic acid and metal binding. The role of glutamic acid residues in coordination of various metal ions was already emphasized in sections discussing ion channels. A few other illustrative examples are listed below. Based on the analysis of the complexes formed between integrins (which are central molecules in the adhesion processes that mediate cell-cell and cell-extracellular group giving rise to the pyrrolidone carboxylic acid (pyro-Glu). However, it was emphasized that pyro-Glu is exclusively found at the N-terminal end of the thermal polymers when glutamic acid is a predominant amino acid in a mixture of amino acids subjected to thermal polymerization. 129 Another important glutamic acid-based PTM is gammacarboxylation catalyzed by the vitamin K-dependent carboxylase that transforms specific glutamate residues in proteins to gammacarboxy glutamic acid (Gla) in the presence of reduced vitamin K, molecular oxygen and carbon dioxide. 130 This modification is widely distributed in the animal kingdom and has a wide range of physiological implications, such as hemostasis, bone calcification and signal transduction. 130 In addition to be a target for various PTMs, glutamic acid itself can be used as an important protein modifier, giving raise to polyglutamylation, which is a specific PTM where polyglutamate chains of variable lengths are added to the modified protein. 131 Polyglutamylation is evolutionarily conserved and is commonly found in the microtubule (MT) building block, tubulin. This PTM, being primarily found within the tubulin C-terminal tail that participates in binding of many structural and motor MT-associated proteins, is believed to be c