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

Uversky, Vladimir N

Glutamic acids inside the pores of ion channels. Being negatively charged at physiological pH, glutamic acid is perfectly suited for binding metal ions. This property is used in specific regulation of a variety of ion channels. For example, in cyclic nucleotide-gated (CNG) channels (which are found in vertebrate photoreceptors and olfactory epithelium, 77 elsewhere in the nervous system [78] [79] [80] and in a variety of other cell types including kidney, testis and heart, 81 and whose activation represents the final step in the transduction pathways in both vision and olfaction [82] [83] [84] ), a single glutamic acid strategically located in the pore represents the binding site for multiple monovalent cations, the blocking site for external divalent cations and the site for the effect of protons on permeation. 82 This is not too surprising since the pore region of the channel controls both the singlechannel conductance and the pore diameter of the channel. 85 Importantly, CNG channels are permeable to Ca 2+ , which is an important element in the activation of intracellular targets, and which in addition to permeating CNG channels can profoundly block the current flow carried by monovalent cations through the CNG channels. 83 This capability of Ca 2+ to block the monovalent cation flow is determined by the high-affinity binding of Ca 2+ to a single acidic amino acid residue located in the pore of the channel, which is Glu363 for the rod CNG channel and Glu333 for the catfish olfactory CNG channel. 86 This same glutamic acid residue is also responsible for the external rapid proton block of CNG channels, another characteristic that the CNG channels share with Ca 2+ channels. 86 Glutamic acid also plays an important regulatory role in the voltage-dependent calcium channels that are located in the plasma membrane and form a highly selective conduit by which Ca 2+ ions enter all excitable cells and some nonexcitable cells. 87 For these channels to operate, Ca 2+ ions must enter selectively through the pore, bypassing competition with other extracellular ions. The high selectivity of a unique Ca 2+ filter is determined pathway for protons utilized in the catalytic NO reduction; the carboxylate group of Glu215, which is located at the backside of Glu211, contributes to the electro-negative environment of the binuclear center of cNOR, and to the low redox potential of heme b 3 iron; finally Glu135 and Glu138 are positioned in the loop connecting the transmembrane helices III and IV, with Glu135 serving as one of the Ca 2+ ligands (which is crucial for maintaining the configuration of heme b and b 3 ) and assisting in the water-mediated proton transfer through interactions with a number of water molecules, and with Glu138 serving as a key residue for maintaining the unique conformation of the long loop through interactions with the residues in transmembrane helix II, which would stabilize the coordination of Glu135 to Ca 2+ . 100 Mono-ADP-ribosyltransferase, which is responsible for the mono-ADP-ribosylation of proteins, possesses a critical glutamic acid at the catalytic cleft which functions to position NAD for nucleophilic attack at the N-glycosidic linkage for either ADPribose transfer or NAD hydrolysis. 101 The pronounced Na + /K + selectivity of Na,K-ATPase relies on the strategic positioning of glutamic acid residues. 102 Here, intramembrane Glu327 in transmembrane segment M4, Glu779 in M5, Asp804 and Asp808 in M6 are essential for tigh