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
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
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DOI：
10.1074/jbc.m110.156950
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发表时间：
2010-11-19
影响因子：
4.8
通讯作者：
Clausen, Henrik
中科院分区：
文献类型：
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作者：
Schjoldager, Katrine T. -B. G.;Vester-Christensen, Malene B.;Clausen, Henrik
血管生成素样蛋白3（ANGPTL 3）是一种重要的内皮和脂蛋白脂肪酶抑制剂，也是一种有前途的药物靶点。ANGPTL 3经历前蛋白转化酶加工（RAPR（224）向下箭头TT）以活化，并且加工位点含有两个紧邻C-末端的潜在GalNAc O-糖基化位点（TT 226）。我们在CHO ldlD细胞中开发了体内模型系统，其用于显示加工位点中的0-糖基化阻断ANGPTL 3的加工。全基因组SNP关联研究已经将多肽GalNAc转移酶基因GALNT 2鉴定为低HDL和高甘油三酯血液水平的候选基因。我们假设GalNAc-T2转移酶对参与脂质代谢的蛋白质进行关键的O-糖基化。对已知影响脂质代谢的一组蛋白质筛选GalNAc-T2糖基化的潜在位点，鉴定了ANGPTL 3中与前蛋白转化酶加工位点相邻的Thr（226）。我们证明了具有RAPR（224）向下箭头TT加工位点的肽中Thr（226）的GalNAc-T2糖基化阻断了体外弗林蛋白酶切割。该研究表明，ANGPTL 3活化是由O-糖基化调节的，并且该步骤可能由GalNAc-T2控制。
The angiopoietin-like protein 3 (ANGPTL3) is an important inhibitor of the endothelial and lipoprotein lipases and a promising drug target. ANGPTL3 undergoes proprotein convertase processing (RAPR(224) down arrow TT) for activation, and the processing site contains two potential GalNAc O-glycosylation sites immediately C-terminal (TT226). 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. 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. We hypothesized that the GalNAc-T2 transferase performed critical O-glycosylation of proteins involved in lipid metabolism. 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. We demonstrated that GalNAc-T2 glycosylation of Thr(226) in a peptide with the RAPR(224) down arrow TT processing site blocks in vitro furin cleavage. The study demonstrates that ANGPTL3 activation is modulated by O-glycosylation and that this step is probably controlled by GalNAc-T2.