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

Uversky, Vladimir N

tamate accounts for 26.4% (133 out of 504 residues). Similarly, human NF-H (a polypeptide comprising 1,026 residues) has 189 glutamic acids, 143 of which are found in the 613 residues-long C-terminal tail of this protein, whereas in the human NF-L (NF light polypeptide which has 543 residues), there are 99 glutamic acids, with almost half of which (46) being located within the acidic C-terminal subdomain (the last 100 residues of the protein). In addition to neurofilament polypeptides, EBDs were found in microtubuleassociated protein 2 (MAP2) 166 and NuMa. 167 Analysis of the amino acid compositions of these proteins revealed that they follow the trend established by NFs and contain significant amount of glutamic acid residues (220 out of 1,827 residues in human MAP2 are glutamates and there are 291 glutamic acids in the 2,115 residues-long human NuMa). natural biopolymer is nontoxic, biocompatible and nonimmunogenic. It can be produced by various bacterial strains in a controllable way. 152 As a result, PGA is commonly used in cosmetics/ skin care, bone care, nanoparticle for drug delivery system, hydrogel, etc. 154 For example, the PGA-based Medusa system has been recently developed for slow release of therapeutic proteins and peptides. 155 Here, a poly L-glutamate backbone is grafted with hydrophobic α-tocopherol molecules, creating a colloidal suspension of nanoparticles in water that contain hydrophobic nanodomains suitable for the reversible binding of various drug molecules. 155 The potential multifarious applications of PGA in the areas of biomedical materials, drug delivery carriers, and biological adhesives have been studied extensively. 156 In general, γ-PGA is recognized now as an important biomaterial in drug delivery applications, with γ-PGA-based nanoparticles being considered as promising delivery carriers for anticancer therapeutics. 157 Recently, a high molecular weight γ-PGA was shown to be used as an immune-stimulating agent. 154 Finally, conjugation of paclitaxel, a widely used chemotherapeutic agent whose therapeutic index is limited by low tumor exposure and high systemic exposure, with biodegradable poly-lglutamic acid generates paclitaxel poliglumex (PPX, CT-2103). 158 This macromolecular drug conjugate enhances tumor exposure to the drug, since the release of paclitaxel from the polymeric backbone was shown to be dependent on the PPX degradation by the lysosomal protease cathepsin B, which is upregulated in many tumor types. 158