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

Uversky, Vladimir N

by the four glutamic acid residues located at homologous positions within each of the four pore-forming segments and which form a single or multiple Ca 2+ -binding site(s) that entrap calcium ions, thus giving them a possibility to be electrostatically repulsed through the intracellular opening of the pore. 87 In the bacterial KcsA and inwardly rectifying K + (Kir) channels, glutamic acid is also involved in the action of the selectivity filter. 88 Here, the network of residues stabilizing the pore of KcsA involves a Glu71-Asp80 carboxyl-carboxylate interaction behind the selectivity filter, whereas the structure of the pore in Kir channels is stabilized by a Glu-Arg salt bridge. 88 Therefore, although Glu is quite conserved among both types of channels, the network of interactions is not translatable from one channel to the other. This clearly shows that different potassium channels are characterized by diverse gating patterns. 88 The presence of a highly conserved glutamic acid residue in the middle of a transmembrane domain is a characteristic feature of a family of transmembrane glycoproteins with two immunoglobulin-like domains, such as basigin (Bsg, also known as CD147 or EMMPRIN), embigin and neuroplastin. 89 Finally, a critical glutamic acid residue was recently identified in CLC proteins, which constitute a large structurally defined family of Cl − ion channels and H + /Cl − antiporters which are found in prokaryotes and eukaryotes, 90 and which perform their functions in the plasma membrane or in various intracellular organelles such as vesicles of the endosomal/lysosomal pathway or in synaptic vesicles. 91 Mutations in human CLC channels are known to cause a set of very diverse diseases such as myotonia (muscle stiffness), Bartter syndrome (renal salt loss) with or without deafness, Dent's disease (proteinuria and kidney stones), osteopetrosis and neurodegeneration, and possibly epilepsy. 91 The side chain of the aforementioned critical glutamic acid occupies a third Cl − ion binding site in the closed state of the channel and moves away to allow Cl − binding. 90 Glutamic acid valve. Glutamic acid is known to play a unique role in regulation of the cytochrome-c oxidase (CcO) activity. CcO is the last enzyme of the respiratory electron transport chain in mitochondria (or bacteria) located in the inner mitochondrial (or bacterial) membrane, and it is responsible for reducing ~90% of the oxygen taken up in aerobic life. This protein powers the production of ATP by generating an electrochemical proton gradient across the membrane via the catalysis of the oxygen reduction to water that takes place in the binuclear center (BNC) of the enzyme. CcO uses four electrons taken up from the cytochrome c located at the positively charged P-side (outside) of the membrane and four "chemical" protons taken from the negatively charged N-side (inside) to reduce the dioxygen to two water molecules. In addition to this oxygen reduction reaction, four "pump" protons are translocated from the N-side to the P-side across the membrane against the opposing membrane potential, doubling the total amount of charge separated by the enzyme. [92] [93] [94] [95] Therefore, the main role of CcO is to serve as a proton pump and a generator of the electrochemical proton gradient or charge separation across the membrane, which is achieved via two separate processes. First, the reduction of oxygen to water by electrons and protons taken up from opposite sides of