Distinct C- mannosylation of netrin receptor thrombospondin type 1 repeats by mammalian DPY19L1 and DPY19L3

Significance Protein C -mannosylation is restricted to animals and some related species. The C -mannosyltransferases probably evolved from enzymes responsible for N -glycosylation in the endoplasmic reticulum and are therefore expected to provide similar functions. Here we show that mammals have, in contrast to most lower animals, at least two C -mannosyltransferases with different recognition sequences, allowing glycosylation of all three tryptophans in the WxxWxxW motif of thrombospondin repeats, which are small modules found in many different proteins. We demonstrate that one of the C -mannosyltransferases, able to modify two tryptophans, is required and sufficient for the netrin receptor to reach the cell surface.