Proteolytic cleavage driven by glycosylation [Glycobiology and Extracellular Matrices]

October 29th, 2015 by Kotzler, M. P., Withers, S. G.

Proteolytic processing of human Host Cell Factor 1 (HCF-1) to its mature form, was recently shown, unexpectedly, to occur in a UDP-GlcNAc-dependent fashion within the transferase active site of O-GlcNAc Transferase (OGT) (Science 342, 1235-1239). An interesting mechanism involving formation and then intramolecular rearrangement of a covalent glycosyl ester adduct of the HCF-1 polypeptide was proposed to account for this unprecedented proteolytic activity. However the key intermediate remained hypothetical. Here, using a model enzyme system for which the formation of a glycosyl ester within the enzyme active site has been shown unequivocally, we show that ester formation can indeed lead to proteolysis of the adjacent peptide bond, thereby providing substantive support for the mechanism of HCF-1 processing proposed.