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

Uversky, Vladimir N

e. 185 Based on these observations, it has been proposed that pH-controlled membrane permealization induced by GALA can serve as a model for the design of environmentally responsive peptidic vehicles for drugs and genes delivery. 185 Other type of PESTs: PTP-PESTs. Protein tyrosine phosphatases (PTP) with proline-, glutamate-, serine-and threoninerich sequence, PTPs-PEST, are a ubiquitously expressed critical regulators of cell adhesion and migration. 186, 187 This family of PTPs includes three intracellular phosphatases known as prolineenriched phosphatase (PEP) in mice or lymphoid tyrosine phosphatase (LYP) in humans (also known as PTPN22 and PTPN8), PTP-PEST (also referred to as PTPN12) and PTP-hematopoietic stem cell fraction (PTP-HSCF, which is also known by several other names, such as also termed brain-derived phosphatase 1 (BDP1), PTP20, PTP-K1, fetal liver phosphatase 1 (FLP1) and PTPN18. 186 All these phosphatases possess a common structural organization that includes an N-terminally located phosphatase domain, followed by a highly divergent central region that contains various motifs for interactions with other proteins, and a conserved C-terminal domain known as carboxyl-terminal homology (CTH) domain. 186 Human PTP-LYP (PTPN22/ PTPN8) is a 807 residues-long protein that contains 59 and 40 glutamic and aspartic acids and 45, 83 and 32 prolines, serines and threonines, respectively. Human PTP-PEST (PTPN12) consists of 780 residues and has 67, 49, 66, 72 and 54 glutamates, aspartates, prolines, serines and threonines, respectively, most of Recently, we proposed that EBDs can be used as protein solubility enhancers. 168 In fact, we showed that highly charged protein sequences (both natural and artificial) can act as EBDs, and that translational fusion of such sequences to target proteins can serve as an effective solubilizing means by creating both large favorable surface area for water interactions and large excluded volumes around the partner. 168 This suggests that intrinsically disordered EBDs (which extend away from the partner and sweep out large molecules) can enable the target protein to fold free from interference. 168 All artificial fusions used in our study had low sequence complexity and high net charge, but were diversified using distinctive amino acid compositions and lengths. 168 Among successful solubilizers were artificial EBDs containing the most disorder-promoting residues (Glu, Pro, Gln and Ser) in the proportion Glu:Pro:Gln:Ser = 2:2:1:1; i.e., sequences containing > 33% glutamic acids. 168 Therefore, it seems that glutamic acid is crucial for the successful function of EBD-containing proteins.