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

Uversky, Vladimir N

Proteins with long simple repeat elements from herpesviruses. One of the mechanisms employed by herpesviruses to evade the immune response, allowing them to persist life-long in their hosts, relies on the use of specific proteins that function as cis-acting inhibitors of antigen presentation. 234 Among these inhibitors are the nuclear antigen 1 (EBNA1) and pGZr in the Epstein-Barr virus (EBV) and the latency-associated nuclear antigen 1 (LANA1) of the Kaposi sarcoma herpesvirus. 234 The common feature of all these proteins is the presence of long simple repeat elements in their amino acid sequences. For example, pGZr is a 230 amino-acids long glycine, glutamine, and glutamic acid-rich repeat ("GZ" repeat) protein that which is encoded by a large nested open reading frame located in the EBNA1 mRNA and is highly similar (65% amino-acid identity) to the acidic repeat of LANA1. 234 Latent nuclear antigen of human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus) is a large (1,036 residues) highly acidic protein (pI 3.81) that contains 237 glutamic acids, 179 glutamines, 114 prolines and 90 aspartic acids. In Herpesvirus saimiri (HVS) that infects squirrel monkeys, the functional homolog of Epstein-Barr virus EBNA1 and Kaposi's sarcoma-associated herpesvirus LANA1 proteins is the 501 residues-long product of the open reading frame 73 known as ORF73 or latency associated nuclear antigen. 235 ORF73 contains a repeat domain composed of a glutamic acid and glycine repeat mutation affects the ability of HLA-DPB1 to present beryllium to pathogenic CD4 + T cells. 242 Sickle cell anemia and Glu6Val mutation in hemoglobin. Sicklecell (SCA) or drepanocytosis is an autosomal recessive genetic blood disease with over-dominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. The disease is caused by a single point mutation in the β-globin chain of hemoglobin where the hydrophilic and negatively charged amino acid glutamic acid is replaced by the hydrophobic amino acid valine at the sixth position. As a result of this substitution, sickle hemoglobin polymerizes inside the affected erythrocytes. It was pointed out that such sickle hemoglobin polymerization occurs by homogeneous and heterogeneous nucleation mechanisms, which are both highly sensitive to macromolecular crowding. 243 In fact, the rates of homogeneous nucleation were shown to be enhanced by 10 10 when the initial concentration was augmented by 50% nonpolymerizing hemoglobin. 243 Retinitis pigmentosa and mutations in a Glu-rich domain of RPGR. Retinitis pigmentosa (RP) is an inherited, degenerative eye disease associated with the progressive loss of photoreceptor genes that causes severe vision impairment and often blindness. 244 Among other factors, RP is caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene which accounts for 15-20% of RP cases in Caucasians. 245 Genetic analysis revealed that of 240 RPGR mutations 95% are associated with X-linked retinitis pigmentosa (XLRP), 3% are found in cone, cone-rod dystrophy or atrophic macular atrophy, and 2% are related to syndromal retinal dystrophies with ciliary dyskinesia and hearing loss. 245 Importantly, all disease-causing mutations occur in one or more RPGR isoforms containing the C-terminal exon open reading frame 15 (ORF15), and 55% occur in a Glu-rich domain within exon ORF15, which accounts for only 31% of the protein. 245 RPGR (1,020 residues) contains 123 glutamic aci