C-Mannosylation: A Modification on Tryptophan in Cellular Proteins

Abstract

C-Mannosylation is a unique glycosylation in which an a-mannose attaches to the indole C2 carbon atom of a tryptophan (Trp) residue to produce C-mannosyl-tryptophan. C-Mannosylation usually occurs at the first Trp in the consensus amino acid sequence Trp-x-x-Trp (W-x-x-W) in proteins through an enzymatic reaction with a specific mannosyltransferase. Recently, Caenorhabditis elegans DPY-19 was identified as a C-mannosyltransferase. Most substrates for C-mannosylation are part of either the thrombospondin type-1 repeat (TSR) superfamily or the type I cytokine receptor family, suggesting a functional role for C-mannosylation in specific substrate proteins. Although the functions of C-mannosylation have not been fully clarified, site-directed mutagenesis of the C-mannosylation potential site in the W-x-x-W motif has revealed it to be important in the folding or targeting of substrate proteins, such as mucins and ADAMTS-like 1, in the cell. By using chemically synthesized C-mannosylated TSR-derived peptides, it was revealed that C-mannosylated peptides could modulate lipopolysaccharide-induced cellular signaling to produce tumor necrosis factor-a. These accumulated findings indicate that C-mannosylation plays important roles in modulating the functions of acceptor proteins in the cell.