O-Fucosylation of Proteins

Abstract

l-Fucose is typically a terminal modification on N-linked or mucin-type O-linked glycans, but l-fucose can also be directly α-linked to the hydroxyl group of serine or threonine residues termed O-fucose. Here we describe the discovery of O-fucose modifications in three different contexts: Epidermal Growth Factor-like (EGF) repeats, Thrombospondin Type-1 repeats (TSRs), and nuclear and cytoplasmic proteins. Both EGF repeats and TSRs are small, cysteine-rich motifs found in numerous secreted and cell surface proteins. O-Fucose is added to EGF repeats by protein O-fucosyltransferase 1 (POFUT1), while a POFUT1 homolog, POFUT2, adds O-fucose to TSRs. O-Fucose on EGF repeats can be elongated to a disaccharide by β3-GlcNAc transferases of the Fringe family, while O-fucose on TSRs can be modified with a glucose by β3-glucosyltransferase (B3GLCT). Interestingly, both POFUT1 and POFUT2 modify folded structures and are localized to the ER which has led to the proposal that they function in quality control pathways for folding of EGF repeats and TSRs, respectively. Most recently, nuclear and cytoplasmic proteins in plants and protists have been shown to be O-fucosylated by SPINDLY, a homolog of O-GlcNAc transferase. Here we discuss the structure, biosynthesis, and function of O-fucose modifications in these three contexts.