A mannose sugar is added to the first tryptophan residue in the sequence W&ndash;X&ndash;X&ndash;W (W indicates tryptophan; X is any amino acid). A C-C bond is formed between the first carbon of the alpha-mannose and the second carbon of the tryptophan. However, not all the sequences that have this pattern are mannosylated. It has been established that, in fact, only two thirds are and that there is a clear preference for the second amino acid to be one of the polar ones (Ser, Ala, Gly and Thr) in order for mannosylation to occur. Recently there has been a breakthrough in the technique of predicting whether or not the sequence will have a mannosylation site that provides an accuracy of 93% opposed to the 67% accuracy if we just consider the WXXW motif.
Thrombospondins are one of the proteins most commonly modified in this way. However, there is another group of proteins that undergo C-mannosylation, type I cytokine receptors. C-mannosylation is unusual because the sugar is linked to a carbon rather than a reactive atom such as nitrogen or oxygen. In 2011, the first crystal structure of a protein containing this type of glycosylation was determined—that of human complement component 8. Currently it is established that 18% of human proteins, secreted and transmembrane undergo the process of C-mannosylation. Numerous studies have shown that this process plays an important role in the secretion of Trombospondin type 1 containing proteins which are retained in the endoplasmic reticulum if they do not undergo C-mannosylation This explains why a type of cytokine receptors, erythropoietin receptor remained in the endoplasmic reticulum if it lacked C-mannosylation sites.