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

Uversky, Vladimir N

verse ligands relies on specific glutamic-acid-or aspartic-acid-based sequence motifs that function in a divalent cation-dependent and conformationally sensitive manner. 118 The levels of intracellular zinc in living cells are crucial for managing various cellular processes, such as growth, development and differentiation. Zinc is involved in protein, nucleic acid, carbohydrate and lipid metabolism and also plays a role in the control of gene transcription and the coordination of other biological processes controlled by proteins containing DNA-binding zinc finger motifs, RING fingers and LIM domains. 119 The physiologically relevant intracellular levels of zinc are controlled by specific zinc transporters which mostly transport zinc into cells from outside. 105 Members of one of the subfamilies of these transporters, LIV-1 subfamily of ZIP zinc Transporters (LZT), being similar to other ZIP transporters in secondary structure and ability to transport metal ions across the plasma membrane or intracellular membranes, possess a unique HEXPHEXGD motif containing conserved proline and glutamic acid residues, that fits the consensus sequence for the catalytic zinc-biding site of matrix metalloproteinases (HEXXHXXGXXH), and which is unprecedented in other zinc transporters. 105 In addition to this set of specific examples, one should keep in mind that all structures of the Ca 2+ -binding domains have in common a high negative surface potential usually associated with Asp or Glu residues. 120 Therefore, important glutamic acid residues responsible for calcium coordination can be found in various members of the major Ca 2+ -binding proteins, such as EF-hand domains, EGF-like domains, γ-carboxyl glutamic acid (GLA)-rich domains, cadherin domains, Ca 2+ -dependent (C)-type lectin-like domains and Ca 2+ -binding pockets of family C G-protein-coupled receptors. 120 A particularly intriguing role was described for the N-terminal glutamic acid residues in the canonical Ca 2+ -protein, α-lactabumin, 121 which is frequently used as a model protein in folding studies and in studies on the effect of calcium binding on protein structure, stability and folding. For example, In nudix hydrolases (which is a family of Mg 2+ -requiring enzymes that catalyze the hydrolysis of nucleoside diphosphates linked to other moieties) there is a specific motif, Nudix box (GX 5 EX 7 REUXEEXGU, where U is a bulky hydrophobic residue), that forms a loop-α helix-loop structural motif that functions as a common Mg 2+ -binding and catalytic site. 111 It was emphasized that the overall catalytic powers of Nudix hydrolases consists in accelerating the reaction rate by 10 9 to 10 12 times. The reactions are accelerated 10 3 -10 5 -times by general base catalysis by a glutamate residue within, or beyond the Nudix box, or by a histidine beyond the Nudix box. The additional 10 3 -10 5 -fold rate acceleration is due to the Lewis acid catalysis provided by one, two, or three divalent cations. One divalent cation is coordinated by two or three conserved residues of the Nudix box, the initial glycine and one or two glutamate residues, together with a remote glutamate or glutamine ligand located outside the Nudix box. 111 Glutamic acids at various binding sites. Hemopexin is an important multifunctional plasma protein involved in the sequestering of heme released into the plasma from hemoglobin and myoglobin as the result of intravascular or extravascular hemolysis and due to skeletal mus