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

Uversky, Vladimir N

Pcp4l1. Purkinje cell produces two closely related proteins containing IQ motifs, Purkinje cell protein 4-like 1 (Pcp4l1) and Pcp4/PEP-19. Although Pcp4/PEP-19 is able to interact with calmodulin and inhibit calmodulin-dependent enzymes, and although the synthetic peptide constituting only the IQ motif of Pcp4l1 binds calmodulin and inhibits calmodulin-dependent kinase II, the full-length Pcp4l1 does not interact with calmodulin. 241 The lack of ability of the full length Pcp4l1 to interact with calmodulin was ascribed to its nine-residue glutamic acid-rich sequence that lies outside the IQ motif in Pcp4l1. Mutational analysis showed that calmodulin binding can be restored not only by the deletion of this inhibitory motif, but also by exchanging it with the homologous region of PEP-19 and by simple point mutation converting a single isoleucine (Ile36) within this motif to phenylalanine or to other aromatic residues. 241 Therefore, although PEP-19 and Pcp4l1 possess noticeable sequence similarities, their functional properties are very different due to the presence of the Glu-rich element in Pcp4l1 that can functionally suppress an IQ motif. 241 Glutamic acid mutations and human diseases. Chronic beryllium disease and Lys96Glu mutation in HLA-DPB1. Chronic beryllium disease (CBD) is a hypersensitivity disorder that affects 2-16% of workers professionally exposed to berillium in the workplace. CBD is characterized by a granulomatous inflammation and accumulation of beryllium-specific CD4 + T cells in the lung. 242 The susceptibility to this disease depends on both genetic factors (genetic susceptibility) and the nature of the exposure. Genetic analysis revealed that a single point mutation at the 69th position of the human leukocyte antigen (HLA) class II histocompatibility antigen DP β 1 chain (HLA-DPB1), where lysine is substituted by a glutamic acid, makes the carriers more susceptible to CBD. It has been proposed that the K→E point of enzymes, or be related to metal binding. In IDPs/IDPRs, overabundance of glutamic acids defines the extended conformation of native coils and native pre-molten globules. Glutamic acid is an important part of the PEST motif related to protein degradation. It is crucial for function of entropic bristle domains and several chaperones. Stretches of glutamic acid residues have a lot of specific functions that range from unique metal binding properties of phytochelatins and bone phosphoproteins, to regulation of cell adhesion and migration, to defining specific immunochemical reactivity of several antigens.