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

Uversky, Vladimir N

GARPs in rod photoreceptors. Glutamic acid-rich proteins (GARPs) are common in different organisms and have numerous biological functions. For example, rod photoreceptors contain three different glutamic acid-rich proteins (GARPs), two soluble forms, GARP1 and GARP2, and the N-terminal cytoplasmic domain (GARP part) of the B1 subunit of the cyclic GMP-gated channel (also known as cyclic nucleotide-gated cation channel β-1, CNGB1), that are involved in the control of the Ca 2+ propagation from the site of its entry at the cyclic nucleotidegated channel to the cytosol of the outer segment. 204 The cyclic acid-rich domains or regions. For example, the non-epithelial intermediate filament (IF) subunit protein (e.g., human vimentin, which is attached to the nucleus, endoplasmic reticulum and mitochondria, either laterally or terminally and that contains 11.8% glutamic acids) can specifically bind core histones with a stoichiometry of 8 core histones per a nonneuronal IF protein dimer. 194 Glutamic acids clearly play a crucial role in this interaction since the 68 kD neurofilament protein, which was already discussed in the EBD section and contains a glutamic acid-rich C-terminal extension, can bind more core histones per dimer (24 molecules of core histones) than the dimer of the non-neuronal IF proteins. 194 In the nuclei of Physarum polycephalum, there is an alanine, lysine and glutamic acid-rich nuclear protein (P2) with a molecular mass of ~19.5 kDa that can specifically interact with histones and therefore is co-extracted with histones. 195 Based on amino acid sequence analysis, it has been concluded that P2 is a HMG-like protein, which, according to CD measurements, contains only 5% secondary structure and is, therefore, essentially unstructured under in vivo conditions. 195 Titin. The gigantic protein titin (there are 34,350 residues in the human protein) is a key component in the assembly and functioning of vertebrate striated muscles. Among numerous cellular functions of titin (also known as connectin) are contribution to the fine balance of forces between the two halves of the sarcomere which is crucial for the elasticity of muscle cells, as well as participation in chromosome condensation and chromosome segregation during mitosis of non-muscle cells. The ability of titin to reversibly extend relies on a set of PEVK segments, rich in proline (P), glutamate (E), valine (V) and lysine (K) residues. The single molecule analysis of the recombinant titin fragment, containing approximately 28-residue PEVK repeats and glutamic acid-rich motifs, revealed that the bending rigidity of the PEVK fragments can be reduced due to calcium-induced conformational changes. 196 Furthermore, the glutamic acid-rich motif was shown to be critical for this process. Based on these observations, it has been concluded that the glutamic acid-rich motifs embedded into the PEVK segments make titin a calcium-dependent molecular spring that can adapt to the physiological state of the cell. 196 Curiously, titin has 3,193 glutamic acids, 449 of which are found in the glutamic acid-rich region (residues 9974-11917) that contains 31 PEVK motifs. Glutamates are not evenly distributed within the glutamic acid-rich region; e.g., 42 glutamic acids are concentrated within the first 116 residues of this region (residues 9974-10,089). In other words, although the glutamic acid-rich region comprises just 5.6% of the whole titin, it has 14.1% of all the titin's glutamates.