By: Richard D. Cummings
Over 500 different post-translational modifications (PTMs) of amino acids in proteins are now recognized (1). Among the many different types of protein modifications, glycosylation is the most common. While we commonly think of a few such modifications, e.g., GlcNAc-Asn, GlcNAc-Ser/Thr, GalNAc-Ser/Thr, Xyl-Ser, Fuc-Ser/Thr, and Man-Ser/Thr, there many unusual glycopeptides/glycoproteins found in animals, some made by people and others made by different organisms (2, 3). For example, in regard to O-linked fucose (Glcα1-3Fucα1-Ser/Thr), it was first detected as a glycopeptide in human urine in 1975, but the finding was not pursued at the time (4), despite the fact it occurs at relatively high levels- 0.2-0.3 mg/liter of urine. It is now known that O-linked fucose occurs in almost all animal cells and O-fucose glycans participate in both intermolecular and intramolecular interactions (5). The O-GlcNAc modification on intracellular proteins was not known until the mid 1980s, and is now known to regulate a tremendous number of biological pathways (6-8). A large list of other peptide modifications with carbohydrates, which can occur on cytoplasmic/nuclear glycoproteins and those in the secretory pathway, which until a few years ago were not known to occur, can be found in the review by Schjoldager et al (9), and include Glcα1-Tyr, Glcβ-Ser, Galβ-Hyl and many others. Recently, O-linked GlcNAc to Tyr (GlcNAcβ-Tyr) was proven to occur on glycoproteins in human pancreatic tumor cells (10). GlcNAc-Tyr modification was also recently shown to occur by glycosyltransferases in the toxins of Yersiniaenterocolitica and Yersinia kristensenii, which can modify Rho family proteins in cells taking up the toxin (10). Thus, just for Tyr modification, it can be modified to Glc-Tyr, GalNAc-Tyr and GlcNAc-Tyr, and who knows how many other sugars might be linked to Tyr? How many more such unusual modifications of other amino acids remain to be discovered? So far, 10 of the 20 amino acids have been shown to be modified by carbohydrates (11).
Interestingly, several other unusual glycopeptides or glycoamino acids were observed long ago in urine, but not well studied afterward, such as digalactosylcysteine in human urine (12) and triglucosylcysteine in human erythrocytes (13). Lactobacillus plantarum KW30 synthesizes an anti-bacterial glycopeptide (bacteriocin) that contains GlcNAc in S-linkage to cysteine and is essential for its antibacterial activity (14). A rare and interesting modification of serine in some glycoproteins of the cellular slime mold Dictyostelium discoideum is the occurrence of a phosphodiester linkage of GlcNAc to Ser/Thr (GlcNAcα1-P-Ser)(15). Another unusual N-glycosylation occurs in corn where Glc linked to Arg was identified (16).
Interestingly, the enzyme NleB from the enteropathogenic Escherichia coli (EPEC) type III can inhibit host nuclear factor-κB (NF-κB) signaling by adding GlcNAc to a conserved arginine in these death domains of the TNFR1-associated death domain protein (TRADD) (Arg 235 in the TRADD death domain) (17). The NleB-mediated arginine modification with GlcNAc is required for bacterial colonization in the mouse model of EPEC infection.
It is also worth noting another unusual pathway occurring between microbes and their infected animal cell hosts. A bacterium which directly injects proteins into host cells is the mouse pathogen Citrobacter rodentium. It injects the non-LEE-encoded effector A (NleA), which is important in bacterial virulence. When injected into cells, the NleA becomes modified by host cells through addition of O-linked GalNAc, which might represent the first demonstration of O-GalNAc glycosylation by host cells on bacterial glycoproteins (18).
References
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