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

Uversky, Vladimir N

on depends on its protonation state, where the unprotonated residue remains predominantly in a "down" conformation, pointing toward the N side, and therefore facilitating the uptake of a proton, whereas protonation shifts the Glu242 to the "up" conformation, where the side chain of this important residue is swung toward the P side by ~4 Å. 97 Glutamic acid in the active sites of enzymes. In addition to serve multiple structural roles and being involved in regulation of various channels, glutamic acid residues, being positioned within or in the close proximity to the active sites, might have roles in the catalytic activities of various enzymes. One of the illustrative examples of the functional roles of glutamic acid can be found in bacterial nitric oxide reductase (NOR), which is a membraneintegrated enzyme that catalyzes the reduction of nitric oxide NO to nitrous oxide N 2 O using a type of anaerobic respiration where cytotoxic NO is immediately decomposed after its production from nitrite NO 2 − via the nitrite reductase-catalyzed reaction. [98] [99] [100] Three different NOR types are found in bacteria, with the cytochrome c dependent NOR (cNOR) that consists of two subunits, NorB and NorC, being the most extensively studied enzyme. Precise description of the complex catalytic mechanism of this important enzyme is outside the scopes of this review, and therefore only a small piece of the entire picture, where the roles of glutamic acid are emphasized, is briefly described below. The characteristic feature of cNORs is the presence of five conserved glutamic acid residues (Glu135, Glu138, Glu211, Glu215 and Glu280 in P. aeruginosa cNOR) within the NorB subunit consisting of 12 trans-membrane helices and containing the heme b and the binuclear center (heme b 3 /Fe B ) buried in the hydrophobic interior of its trans-membrane region. 100 Here, Glu211 is involved in the coordination of Fe B and its carboxylate functions as the shuttle for catalytic protons from Glu280 to the bound-NO; Glu280, which interacts with Glu211 but is not involved in direct interaction with Fe B , is an important player of the Thr330-Ser277-Glu280-Glu211 network that acts as a delivery matrix communication) and their ligands, it has been concluded that divalent cations are critical for integrin interactions with almost all ligands. Importantly, although divalent cations are bound to integrins, their coordination sphere is not completed and the interactions between integrin and its ligands typically involve completing the metal ion coordination with an acidic ligand residue. 115 For example, complexes between the human intercellular adhesion molecule-1 (ICAM-1) and the I domain of its integrin receptor αLβ2 are stabilized by a critical glutamate residue that completes the magnesium coordination in integrin. 116 Similarly, in the crystal structure of a complex between the I domain of a2b1 integrin and a triple-helical collagen peptide containing a critical GFOGER motif, glutamate residue from the collagen peptide completes the coordination sphere of the I domain metal ion. 117 Based on these observations it has been concluded that a metalglutamate handshake represents a basic mechanism of integrin I domain interaction with its binding partners. 115 Furthermore, it is believed now that the general mechanism by which integrins, these αβ-heterodimeric cell-surface receptors that are vital to the survival and function of nucleated cells, recognize their structurally di