Davis Samuel, Papadopoulos Nick, Aldrich Thomas H, Maisonpierre Peter C, Huang Tammy, Kovac Lubomir, Xu April, Leidich Raymond, Radziejewska Elzbieta, Rafique Ashique, Goldberg Judah, Jain Vivek, Bailey Kevin, Karow Margaret, Fandl Jim, Samuelsson Steven J, Ioffe Ella, Rudge John S, Daly Thomas J, Radziejewski Czeslaw, Yancopoulos George D
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Nat Struct Biol. 2003 Jan;10(1):38-44. doi: 10.1038/nsb880.
Angiopoietins are a recently discovered family of angiogenic factors that interact with the endothelial receptor tyrosine kinase Tie2, either as agonists (angiopoietin-1) or as context-dependent agonists/antagonists (angiopoietin-2). Here we show that angiopoietin-1 has a modular structure unlike any previously characterized growth factor. This modular structure consists of a receptor-binding domain, a dimerization motif and a superclustering motif that forms variable-sized multimers. Genetic engineering of precise multimers of the receptor-binding domain of angiopoietin-1, using surrogate multimerization motifs, reveals that tetramers are the minimal size required for activating endothelial Tie2 receptors. In contrast, engineered dimers can antagonize endothelial Tie2 receptors. Surprisingly, angiopoietin-2 has a modular structure and multimerization state similar to that of angiopoietin-1, and its antagonist activity seems to be a subtle property encoded in its receptor-binding domain.
血管生成素是最近发现的一类血管生成因子家族，它们作为激动剂（血管生成素-1）或作为上下文依赖性激动剂/拮抗剂（血管生成素-2）与内皮受体酪氨酸激酶Tie2相互作用。在此我们表明，血管生成素-1具有一种不同于任何先前已表征生长因子的模块化结构。这种模块化结构由一个受体结合结构域、一个二聚化基序和一个形成大小可变多聚体的超聚集基序组成。利用替代多聚化基序对血管生成素-1受体结合结构域的精确多聚体进行基因工程改造，结果表明四聚体是激活内皮Tie2受体所需的最小尺寸。相比之下，经工程改造的二聚体可拮抗内皮Tie2受体。令人惊讶的是，血管生成素-2具有与血管生成素-1相似的模块化结构和多聚化状态，并且其拮抗活性似乎是编码于其受体结合结构域中的一种微妙特性。
