PMID: 20837471

 

    Legend: Sugar

Title : O-glycosylation modulates proprotein convertase activation of angiopoietin-like protein 3 : possible role of polypeptide GalNAc-transferase-2 in regulation of concentrations of plasma lipids

Abstract :

1. The angiopoietin-like protein 3 ( ANGPTL3 ) is an important inhibitor of the endothelial and lipoprotein lipases and a promising drug target
2. ANGPTL3 undergoes proprotein convertase processing (RAPR(224)↓TT) for activation, and the processing site contains two potential GalNAc O-glycosylation sites immediately C-terminal (TT(226)).
3. We developed an in vivo model system in CHO ldlD cells that was used to show that O-glycosylation in the processing site blocked processing of ANGPTL3
4. Genome-wide SNP association studies have identified the polypeptide GalNAc-transferase gene, GALNT2 , as a candidate gene for low HDL and high triglyceride blood levels
5. We hypothesized that the GalNAc-T2 transferase performed critical O-glycosylation of proteins involved in lipid metabolism
6. Screening of a panel of proteins known to affect lipid metabolism for potential sites glycosylated by GalNAc-T2 led to identification of Thr(226) adjacent to the proprotein convertase processing site in ANGPTL3
7. We demonstrated that GalNAc-T2 glycosylation of Thr(226) in a peptide with the RAPR(224)↓TT processing site blocks in vitro furin cleavage
8. The study demonstrates that ANGPTL3 activation is modulated by O-glycosylation and that this step is probably controlled by GalNAc-T2.