From a single C-mannose to multiple C-mannosyltransferases.

Glycosylation is an evolutionarily conserved post-translational modification of most proteins that are either secreted from cells or remain embedded within membranes as transmembrane proteins. It controls protein stability, plasma half-life, and intracellular trafficking and can contribute to the actual biological function of the protein. Protein glycosylation can be divided into N-linked glycosylation, which refers to the linkage of an oligosaccharide to the amide nitrogen of an asparagine residue; O-glycosylation, which describes attachment of an oligosaccharide to the hydroxyl oxygen of a serine residue or a threonine residue; and C-mannosylation, a rare modification in which a mannose residue is bound to the indole of a tryptophan residue via a carbon-carbon linkage. In this review, we summarize current knowledge about C-mannosylation. We describe how C-mannosylation was initially discovered and on which types of proteins it usually occurs. We explain the operation of the C-mannosyltransferases, the enzymes that attach the mannose to the substrate proteins, and which conformations the C-mannose adopts. Furthermore, we summarize what is known so far about the influence of the C-mannosylation on the function of the actual protein. Our review highlights an often overlooked post-translational modification as an important regulator of protein function.