Ge Hongfei, Yang Guoqing, Huang Lu, Motola Daniel L, Pourbahrami Tiffany, Li Cai
Touchstone Center for Diabetes Research and Departments of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8854, USA.
J Biol Chem. 2004 Jan 16;279(3):2038-45. doi: 10.1074/jbc.M307583200. Epub 2003 Oct 21.
Angiopoietin-like protein 4 (Angptl4) is a recently identified circulating protein expressed primarily in adipose tissue and liver. Also known as peroxisome proliferator-activated receptor (PPAR)-gamma angiopoietin-related, fasting induced adipose factor, and hepatic fibrinogen/angiopoietin-related protein, recombinant Angptl4 causes increase of plasma very low density lipoprotein levels by inhibition of lipoprotein lipase activity. Similar to angiopoietins and other angiopoietin-like proteins, Angptl4 contains an amino-terminal coiled-coil domain and a carboxyl-terminal fibrinogen-like domain. We report here that Angptl4 is evolutionarily conserved among several mammalian species and that full-length Angptl4 protein is an oligomer containing intermolecular disulfide bonds. Oligomerized Angptl4 undergoes proteolytic processing to release its carboxyl fibrinogen-like domain, which circulates as a monomer. Angptl4's N-terminal coiled-coil domain mediates its oligomerization, which by itself is sufficient to form higher order oligomeric structure. Adenovirus-mediated overexpression of Angptl4 in 293 cells shows that conversion of full-length, oligomerized Angptl4 is mediated by a cell-associated protease activity induced by serum. These findings demonstrate a novel property of angiopoietin-like proteins and suggest that oligomerization and proteolytic processing of Angptl4 may regulate its biological activities in vivo.
血管生成素样蛋白4（Angptl4）是一种最近发现的循环蛋白，主要在脂肪组织和肝脏中表达。它也被称为过氧化物酶体增殖物激活受体（PPAR）-γ血管生成素相关蛋白、禁食诱导脂肪因子和肝纤维蛋白原/血管生成素相关蛋白，重组Angptl4通过抑制脂蛋白脂肪酶活性导致血浆极低密度脂蛋白水平升高。与血管生成素和其他血管生成素样蛋白相似，Angptl4包含一个氨基末端卷曲螺旋结构域和一个羧基末端纤维蛋白原样结构域。我们在此报告，Angptl4在几种哺乳动物物种中具有进化保守性，并且全长Angptl4蛋白是一种含有分子间二硫键的寡聚体。寡聚化的Angptl4经过蛋白水解加工以释放其羧基纤维蛋白原样结构域，该结构域以单体形式循环。Angptl4的氨基末端卷曲螺旋结构域介导其寡聚化，其本身足以形成更高阶的寡聚结构。腺病毒介导的Angptl4在293细胞中的过表达表明，全长、寡聚化的Angptl4的转化是由血清诱导的细胞相关蛋白酶活性介导的。这些发现证明了血管生成素样蛋白的一种新特性，并表明Angptl4的寡聚化和蛋白水解加工可能在体内调节其生物学活性。
