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

Uversky, Vladimir N

KIBRA. Kidney and brain protein (KIBRA) is a large (1,113 residues) protein that serves as a potential regulator of the Hippo/ SWH (Sav/Wts/Hpo or Salvador/Warts/Hippo) signaling pathway that restricts proliferation and promotes apoptosis therefore being crucial for tumor suppression. 217, 218 KIBRA has 111 glutamic acids and possesses two N-terminal WW domains, an internal C2-like domain and a C-terminal Glu-rich stretch (residues 819-873). 219 Cellular functions of KIBRA are modulated via phosphorylation by protein kinase C zeta (PRKCZ). 220 Some cellular activities of KIBRA may be associated with memory performance. 220, 221 Furthermore, in mammalian cells, this protein co-activates functions of the dynein light chain 1, 222 is involved in regulation of the collagen-stimulated activation of the ERK/ MAPK cascade 223 and modulates directional migration of podocytes. 224 KIBRA interacts with histone H3 via its Glu-rich region, and this interaction might play an important role in conferring an optimal transactivation function to the estrogen receptor-α (ER) and also may be involved in the proliferation of ligand-stimulated breast cancer cells. 222 SH3BGR. SH3 domain-binding glutamic acid-rich protein (SH3BGR) is a highly acidic (pI 4.09) 239 residues-long protein that possesses 44 glutamates and 15 aspartates and that is expressed in heart and skeletal muscles. 225 The majority of glutamates are located within the C-terminal Glu-rich region (residues 170-239), ~43% of which are glutamic acid residues. In addition to SH3BGR, several other members of the SH3BGR family were found in humans. These are the so-called SH3BGR-like proteins, such as SH3BGRL (114 residues, 12 glutamic acids), SH3BGRL2 (107 residues, 10 glutamic acids) and SH3BGRL3 (93 residues, 7 glutamic acids) encoded by chromosomes Xq13.3 6q13-15, and 1p34.3-35, respectively. 226 It was shown that the SH3 domainbinding glutamic acid-rich-like protein 3 is upregulated in glioblastoma. 227 Also, this protein was noticeably downregulated in nucleotide-gated (CNG) cation channel of rod photoreceptors is a heterotetramer consisting of homologous subunits, α and β (also known as CNGA1 and CNGB1a). CNGA1 is known to be indispensable for channel activation, whereas CNGB1a plays mostly regulatory structural roles. 205 In fact, the N-terminal glutamic acid-rich protein (GARP) domain of CNGB1a and the soluble GARP2 were shown to decrease the opening probability of the CNG channel and therefore these GARPs serve as important autoinhibitors or molecular gate keepers that control the activation of heteromeric rod CNG channels. 205 Furthermore, CNGB1 and GARP2, in concert with a retinal tetraspanin (peripherin-2 or peripherin RDS ), were shown to contribute to the organization of the specific organelle, outer segment (OS), which possesses a characteristic membranous "stacked pancake" architecture that has to be partially renewed daily to maintain cell function and viability. 206 In fact, a mouse knockout of CNGB1 and GARP2 attenuated rod function and caused structural alterations and slowly progressive retinal degeneration. 207 Bovine GARP (or CNGB1) is a 1,394 residues-long transmembrane protein which plays important roles in both visual and olfactory signal transduction. CNGB1 has 209 glutamic acids. GARP1 is a 590-residues-long CNGB1 splice variant that possesses 141 glutamic acids. GARP2 is another CNGB1 splice variant that has 299 residues 38 of which are glutamic acids. Native GARP1 an