Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering
Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering
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DOI：
10.1038/nsb880
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Yancopoulos, GD
中科院分区：
文献类型：
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作者：
Davis, S;Papadopoulos, N;Yancopoulos, GD
血管生成素是最近发现的与内皮受体酪氨酸激酶Tie 2相互作用的血管生成因子家族，其作为激动剂（血管生成素-1）或作为环境依赖性激动剂/拮抗剂（血管生成素-2）。在这里，我们表明，血管生成素-1有一个模块化的结构不同于任何以前的特征生长因子。这种模块化结构由受体结合结构域、二聚化基序和形成可变大小的多聚体的超聚簇基序组成。血管生成素-1受体结合结构域的精确多聚体的基因工程，使用替代多聚化基序，揭示了四聚体是激活内皮Tie 2受体所需的最小尺寸。相反，工程化的二聚体可以拮抗内皮Tie 2受体。令人惊讶的是，血管生成素-2具有类似于血管生成素-1的模块化结构和多聚化状态，并且其拮抗剂活性似乎是在其受体结合结构域中编码的微妙性质。
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 angio, poietin-1, and its antagonist activity seems to be a subtle property encoded in its receptor-binding domain.