Multiple distinct O-Mannosylation pathways in eukaryotes
•Multiple O-Man glycosylation pathways exist in eukaryotes.•Yeast has a unique nucleocytosolic O-Man glycosylation pathway in lieu of the common eukaryotic O-GlcNAc nucleocytosolic pathway.•Cadherin and plexin superfamilies of proteins are major carriers of O-Man glycans.•Congenital disorders of gly...
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| Published in: | Current opinion in structural biology 2019-06, Vol.56, p.171-178 |
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| Main Authors: | , , , , |
| Format: | Article |
| Language: | eng |
| Online Access: | Get full text |
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| Summary: | •Multiple O-Man glycosylation pathways exist in eukaryotes.•Yeast has a unique nucleocytosolic O-Man glycosylation pathway in lieu of the common eukaryotic O-GlcNAc nucleocytosolic pathway.•Cadherin and plexin superfamilies of proteins are major carriers of O-Man glycans.•Congenital disorders of glycosylation are caused by deficiencies in TMTCs.
Protein O-mannosylation (O-Man), originally discovered in yeast five decades ago, is an important post-translational modification (PTM) conserved from bacteria to humans, but not found in plants or nematodes. Until recently, the homologous family of ER-located protein O-mannosyl transferases (PMT1–7 in yeast; POMT1/POMT2 in humans), were the only known enzymes involved in directing O-Man biosynthesis in eukaryotes. However, recent studies demonstrate the existence of multiple distinct O-Man glycosylation pathways indicating that the genetic and biosynthetic regulation of O-Man in eukaryotes is more complex than previously envisioned. Introduction of sensitive glycoproteomics strategies provided an expansion of O-Man glycoproteomes in eukaryotes (yeast and mammalian cell lines) leading to the discovery of O-Man glycosylation on important mammalian cell adhesion (cadherin superfamily) and signaling (plexin family) macromolecules, and to the discovery of unique nucleocytoplasmic O-Man glycosylation in yeast. It is now evident that eukaryotes have multiple distinct O-Man glycosylation pathways including: i) the classical PMT1–7 and POMT1/POMT2 pathway conserved in all eukaryotes apart from plants; ii) a yet uncharacterized nucleocytoplasmic pathway only found in yeast; iii) an ER-located pathway directed by the TMTC1–4 genes found in metazoans and protists and primarily dedicated to the cadherin superfamily; and iv) a yet uncharacterized pathway found in metazoans primarily dedicated to plexins. O-Man glycosylation is thus emerging as a much more widespread and evolutionary diverse PTM with complex genetic and biosynthetic regulation. While deficiencies in the POMT1/POMT2 O-Man pathway underlie muscular dystrophies, the TMTC1–4 pathway appear to be involved in distinct congenital disorders with neurodevelopmental phenotypes. Here, we review and discuss the recent discoveries of the new non-classical O-Man glycosylation pathways, their substrates, functions and roles in disease. |
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| ISSN: | 0959-440X 1879-033X |