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

Uversky, Vladimir N

Glutamic acid is one of the most common natural amino acids and the most abundant amino acid in the diet. Besides being an important component of proteins and polypeptides (see below), being a substrate for the production of the Krebscycle-related α-ketoglutarate intermediate, glutamine and proline, and being the precursor for the synthesis of the inhibitory γ-aminobutyric acid (GABA) in GABA-ergic neurons, glutamate is the principal excitatory neurotransmitter within the vertebrate nervous system. 54 In fact, glutamate is known to act on several different types of receptors and has excitatory effects at ionotropic receptors [such as N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainite, which all incorporate ion channels that are permeable to cations] and modulatory effects at metabotropic receptors [which are G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP]. 54 At chemical synapses of the glutamatergic neurons, glutamate is stored in vesicles and is released from the pre-synaptic cell by nerve impulses. In the opposing post-synaptic cell, binding of glutamate lead to activation of specific glutamate receptors such as NMDA or AMPA. Glutamate plays an important role in synaptic plasticity in the brain and is involved in various cognitive functions, such as learning and memory. 55 In fact, long-term potentiation (one of the plasticity forms) takes place at glutamatergic synapses in the neocortex, hippocampus and other parts of the brain. 55 Another important role of glutamate is its ability to generate volume transmission, where extrasynaptic signaling is created via the summation of glutamate released from a neighboring synapse. 56 In addition to glutamate receptors, neuronal and glial membranes contain glutamate transporters that are responsible for rapid remove of glutamate from extracellular space. 57 Under stress conditions (such as brain injury or disease), glutamate transporters work in reverse leading to the accumulation of considerations with the recent report showing that IDP affinities are tuned mostly by association rates 45 suggests that the degree of pre-adoption of binding conformations in IDPs has to be limited, but not unfavorable.