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

Uversky, Vladimir N

Some of these interactions can induce a disorder-order transition in the entire IDP or in its part. 5, [9] [10] [11] [12] 15, 23, [30] [31] [32] [33] [34] [35] [36] Furthermore, intrinsic disorder opens a unique capability for one protein to be involved in interaction with several unrelated binding partners and to gain different bound structures. 22, 37 Some IDPs can form highly stable complexes; others are involved in signaling interactions where they undergo constant "bound-unbound" transitions, thus acting as dynamic and sensitive "on-off" switches. These proteins typically return to their intrinsically disordered state after the completion of a particular function. Many of the IDPs/IDPRs can gain different conformations depending on the environmental peculiarities. 30, 37 All this constitutes an important arsenal of the unique physiological properties of IDPs/IDPRs that determines their ability to exert different functions in different cellular contests according to a specific conformational state. 8 The folding-at-binding principle is believed to help IDPs or IDPRs to obtain maximal specificity in a protein-protein interaction without very high affinity. 20 This combination of high specificity with low affinity defines the broad utilization of intrinsic disorder in regulatory interactions where turning a signal off is as important as turning it on. 10 Although some partial folding during the IDP/ IDPR-based interactions is a widespread phenomenon, with significant fraction (~1/3) of the interacting residues in IDPs/IDPRs adopting α-helix, β-strand and irregular structures, 31, 32 there are still many other IDPs/IDPRs that are involved in the formation of "fuzzy complexes," where an IDP/IDPR keeps a certain amount of disorder in its bound conformation. 35, [38] [39] [40] Often, the interacting regions in IDPs are observed as loosely structured fragments in their unbound forms. These disorderbased binding sites are known as molecular recognition elements or features (MoREs or MoRFs), 30, 31 preformed structural elements 41 or pre-structured motifs (PreSMos). 42 Although the existence of such loosely structured regions suggests that IDPs can adopt their bound structure(s) at a free-energy cost that is not too high, it is important to remember that increasing the stability of the bound conformation does not necessarily enhance the binding affinity. 23 Another important feature of the disorder-based interactions is their increased speed due to the greater capture radius and the ability to spatially search through interaction space (the so-called "fly-casting" mechanism) 43 and to the fact that fewer encounter events are required for the binding because of lack of orientational restrains. 44 Linking all these form at pHs greater than its pK a 4.6 (and thus Glu is negatively charged at the physiological pH ranging from 7. 35-7.45) . Therefore, glutamic acid is one of two acidic amino acids found in proteins that play important roles as general acids in enzyme active centers, as well as in maintaining the solubility and ionic character of proteins. In fact, glutamic acid residue has a nonpolar surface of 69 Å 2 , and the estimated hydrophobic effect associated with the burial of this residue is 1.74 kcal/mol. 52 In ordered proteins, glutamic acids are predominantly located on protein surface so that they have access to the solvent. In fact, 93% of glutamic acids in known structures of folded proteins are classified as exposed since they ha