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

Uversky, Vladimir N

The side chains of glutamic acid residues are subjected to several PTMs. Some cytoplasmic and nuclear proteins are known to be methylated, i.e., enzymatically modified by the addition of methyl groups from S-adenosylmethionine. Methylation reactions typically occur on carboxyl groups (such as the side chain of glutamic acid) and modulate the activity of the target protein. Glutamate methyl ester formation plays a major role in chemotactic signal transduction in prokaryotes. For example, methyl-accepting chemotaxis proteins are a family of chemotactic-signal transducers that respond to changes in the concentration of attractants and repellents in the environment, transduce a signal from the outside to the inside of the cell, and facilitate sensory adaptation through the variation of the level of methylation. 126, 127 In some proteins and peptides, glutamic acids can be amidated. Also, some glutamine residues in proteins undergo spontaneous (nonenzymatic) deamidation to glutamate with rates that depend upon the sequence and higher-order structure of the protein. Functional groups within the protein can catalyze this reaction, acting as general acids, bases, or stabilizers of the transition state. 128 In rare cases, glutamate residues can be modified by cyclization via condensation of the α-amino group with the side-chain carboxyl neutral pH was shown to be accompanied by the instantaneous formation of a gel-like precipitate with intermolecular antiparallel β-structure. 139 In bacteria, PGA may be composed of only D-, only L-or both D-and L-glutamate enantiomers, and PGA filaments may be poly-γ-L-glutamate filaments (PLGA), PDGA filaments or poly-γ-L-D-glutamate (PLDGA) filaments. 135 The production and maintenance of sufficient D-glutamate pool levels required for the normal bacterial growth is controlled by the glutamate racemase, which is a member of the cofactor-independent, twothiol-based family of amino acid racemases. 140 This enzyme is conserved and essential for growth across the bacterial kingdom and has a conserved overall topology and active site architecture. Therefore, it represents an attractive target for the development of specific inhibitors that could act as possible therapeutic agents. 140 In Gram-negative bacteria, the complex responsible for the polyglutamate synthesis is encoded in specific loci. If the PGA is associated with the bacterial surface and forms a capsule, then the corresponding genes are named cap (for "capsule"); however, if the PGA is released, then the corresponding genes are named pgs (for polyglutamate synthase). 135 The minimal gene sets contain four genes termed cap or pgs B, C, A and E, with all cap genes and the four pgs genes (pgsB, pgsC, pgsAA, pgsE) being organized into operons. 141 Since PGA is an IDP, whose biochemical and biophysical properties are environment-dependent, and since PGA can be found in an anchored to the bacterial surface form or in a released form, this biopolymer can play different roles in different organisms and in different environments. 135 For example, when anchored to the bacterial surface, PGA forms a capsule and act as a virulence factor. 135, 142 In fact, the virulence of Bacillus anthracis (a Gram-positive sporulating bacterium, which is the causal agent of anthrax) was found to be determined by its capsule composed solely of PGA. 143 Similarly, the virulence of Staphylococcus epidermidis (another Gram-positive bacterium that causes severe infection after penetra