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Protein O-mannosylation (O-Man) is a crucial post-translational modification with newly discovered pathways in eukaryotes. These pathways are vital for cell adhesion and signaling, and their dysregulation is linked to diseases like muscular dystrophy and neurodevelopmental disorders.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Glycobiology

Background:

  • Protein O-mannosylation (O-Man) is a conserved post-translational modification (PTM) essential in eukaryotes, originally identified in yeast.
  • The ER-located protein O-mannosyl transferases (PMT/POMT) were long considered the sole enzymes responsible for O-Man biosynthesis.
  • Recent advancements reveal a more complex regulatory network with multiple distinct O-Man glycosylation pathways.

Purpose of the Study:

  • To review and discuss the recent discoveries of novel O-Man glycosylation pathways in eukaryotes.
  • To elucidate the substrates, functions, and disease relevance of these newly identified pathways.
  • To highlight the expanding understanding of O-Man's role in cellular processes and human health.

Main Methods:

  • Glycoproteomics strategies were employed to expand the O-Man glycoproteome.
  • Comparative analysis of conserved and novel O-Man pathways across different species.
  • Review of existing literature on O-Man pathways, substrates, and associated diseases.

Main Results:

  • Discovery of O-Man glycosylation on key mammalian cell adhesion (cadherin) and signaling (plexin) molecules.
  • Identification of a unique nucleocytoplasmic O-Man pathway in yeast.
  • Characterization of ER-located TMTC1-4 pathway in metazoans/protists and a distinct plexin-dedicated pathway in metazoans.
  • O-Man glycosylation is revealed as a widespread, evolutionarily diverse PTM with complex regulation.

Conclusions:

  • Eukaryotes possess multiple distinct O-Man glycosylation pathways beyond the classical POMT pathway.
  • These pathways, including the TMTC1-4 and plexin-dedicated routes, are crucial for diverse cellular functions.
  • Defects in O-Man pathways are implicated in human diseases such as muscular dystrophies and congenital neurodevelopmental disorders.