Abstract
Protein C-Mannosylation is unique in that an α-mannose attaches directly to the indole C2 carbon atom of a Trp residue through a C-C bond. C-Mannosylation usually occurs at the first tryptophan in the consensus amino acid sequence Trp-x-x-Trp (W-x-x-W) through an enzymatic reaction with a specific mannosyltransferase, which has yet to be identified. Most substrates for C-mannosylation are part of either the thrombospondin type-1 repeat (TSR) superfamily or cytokine receptor family, suggesting a functional role for C-mannosylation in specific substrates. Site-directed mutagenesis in the W-x-x-W motif has revealed C-mannosylation to be important in the folding or targeting of substrate proteins, such as mucins and ADAMTS-like 1, in the cell. Furthermore, using chemically synthesized C-mannosylated TSR-derived peptides, Hsc70 was identified as a protein bound to C-mannosylated peptides, and the interaction enhanced the TNF-α-producing signaling by Hsc70 in macrophage-like cells. These recent findings suggest that the C-mannosylation of specific target proteins plays pivotal functional roles in the cell.
