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

Uversky, Vladimir N

t binding of K + and Na + , whereas Asn324 and Glu327 in M4, together with Thr774, Asn776 and Glu779 in the 771-YTLTSNIPEITP motif of M5 contribute to the Na + / K + selectivity. 102 In the family of thiamin diphosphate enzymes, a highly conserved glutamate is known to promote the C 2 -H ionization and the thiamin diphosphate activation. 103 The direct catalytic role of glutamic acid can be seen in matrix metalloproteinases, which are ubiquitous endopeptidases characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid that acts as a general base. 104 For example, one of the wellknown zinc-binding metalloproteases that uses a glutamic acid residue as the fourth ligand to coordinate the zinc ion is thermolysin. In thermolysin, glutamic acid is 20 amino acids downstream from the second histidine in the first motif and present in a small conserved motif (NEXXSD). 105 In the zincin and PDF groups of metalloproteases, the catalytic zinc-binding site contains the HEXXHXXG motif. 105 Also, a glutamic acid residue may be catalytically active in the substrate-binding cleft of plant lysozymes. 106 Each enzyme in the α-amylase family of multidomain hydrolases and transferases has one glutamic acid and two aspartic acid residues necessary for activity. 107 The irreversible dealkylation reaction catalyzed by the O 6 -alkylguanine-DNA alkyltransferase (AGT) that directly repairs alkylation damage at the O 6 -position of guanine is accomplished by an active-site cysteine that participates in a hydrogen bond network with invariant histidine and glutamic acid residues, reminiscent of the serine protease catalytic triad. 108 The spore germination protease (GPR) that degrades small, acid soluble proteins (SASP) protecting spore's DNA against damage, is a structurally and functionally unique protease that utilizes glutamic acid residue to catalyze SASP degradation. 109 In the hydrolytic aldehyde dehydrogenases (ALDHs), catalytic but flexible glutamic acid residues located within the active site serve as the general base that activates the hydrolytic water molecule in the deacylation step. 110 to the net translocation of one electrical charge across the membrane per electron consumed. Second, an additional proton is translocated vectorially across the membrane for each electron consumed, resulting in a net transport of two electrical charges per electron. 96 The protons for the chemical reaction are extracted from the N-side of the membrane via two proton pathways, the D-and K-channels. The D-channel starts at a highly conserved residue, Asp 91 (bovine numbering; subunit I) near the N side, and continues to another highly conserved residue Glu242 that donates protons to the BNC, whereas the key residue in the K-channel is a highly conserved lysine (K319). 95 The D-channel is responsible for the delivery of four "pump" protons that are first transferred from Glu242 to a "loading" site above the BNC and then delivered to the P side via a proton-exit channel. The mystery of this mechanism is in the ability of Glu242 located at the end of the D-channel to somehow sort "pump" protons from "chemical" protons. 95 To explain this behavior, the glutamate valve model has been proposed according to which the side chain of Glu242 shuttles between a state protonically connected to the D channel, and a state connected to the BNC and the pump site. 97 In this proton valve model, the Glu242 moti