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- Title
Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering.
- Authors
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
- Abstract
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.
- Publication
Nature structural biology, 2003, Vol 10, Issue 1, p38
- ISSN
1072-8368
- Publication type
Journal Article
- DOI
10.1038/nsb880