A Systematic Study of Site-specific GalNAc-type O-Glycosylation Modulating Proprotein Convertase Processing

Abstract

Background: GalNAc-type O-glycosylation is emerging as a co-regulator of proprotein convertase processing of proteins. Results: O-Glycosylation within at least Ϯ3 residues of the RXXR substrate motif for furin affected processing. Conclusion: Site-specific O-glycosylation by 20 polypeptide GalNAc transferases have wide co-regulatory functions in proprotein processing. Significance: This is the first systematic study that paves the way for wider co-regulatory functions of O-glycosylation in protein processing.

O-Glycosylation of a Secretory Granule Membrane Enzyme Is Essential for Its Endocytic Trafficking

“…The transfer of GalNAc from UDP-N-acetylgalactosamine onto Ser and Thr residues in target proteins is catalyzed by a large family of polypeptide GalNAc transferases (8). Transcriptomic analysis demonstrated significant levels of expression of seven GalNAc transferases in AtT-20 cells (1, 2, 9 -12, 18) (data not shown).…”

“…Recent studies have demonstrated a role for O-glycans in controlling prohormone convertase processing of FGF 23 (8,10), Tango-1 (9), pro-brain natriuretic peptide (56), and angiopoietin-like protein-3 (ANGPTL3) (57). Lacking O-glycans in exon 16, a 68-kDa product that contained part of exon 16, PAL, the transmembrane and cytosolic domains of PAM, was generated from PAM-1/OSX.…”

Carbamidomethylation Side Reactions May Lead to Glycan Misassignments in Glycopeptide Analysis

“…There is growing evidence that glycosylation may influence biological processes in a site-specific manner [17][18][19], and thus, there is a growing need for the analysis of intact glycopeptides. Recent technical developments, such as the introduction of electron-transfer dissociation (ETD) [20] and new, high sensitivity instrumentation equipped with ETD have made large scale glycopeptide analysis a reality [21,22].…”

Moving the O-glycoproteome from form to function

“…For example, proteolytic processing via proprotein convertase cleavage at RXXR processing sites is prevented if specific nearby Ser or Thr residues are modified with O-GalNAc (10). Addition of O-GalNAc to the lipase inhibitor protein ANGPTL3 by GalNAc-T2 prevents processing and activation by proprotein convertase.…”