Protein -Fucosyltransferases: Biological Functions and Molecular Mechanisms in Mammals.

Domain-specific -fucosylation is an unusual type of glycosylation, where the fucose is directly attached to the serine or threonine residues in specific protein domains via an -linkage. -fucosylated proteins play critical roles in a wide variety of biological events and hold important therapeutic values, with the most studied being the Notch receptors and ADAMTS proteins. -fucose glycans modulate the function of the proteins they modify and are closely associated with various diseases including cancer.

FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains.

O-Fucosylation plays crucial roles in various essential biological events. Alongside the well-established O-fucosylation of epidermal growth factor-like repeats by protein O-fucosyltransferase 1 (POFUT1) and thrombospondin type 1 repeats by POFUT2, we recently identified a type of O-fucosylation on the elastin microfibril interface (EMI) domain of Multimerin-1 (MMRN1). Here, using AlphaFold2 screens, co-immunoprecipitation, enzymatic assays combined with mass spectrometric analysis and CRISPR-Cas9 knockouts, we demonstrate that FUT10 and FUT11, originally annotated in UniProt as α1,3-fucosyltransferases, are actually POFUTs responsible for modifying EMI domains; thus, we renamed them as POFUT3 and POFUT4, respectively.