Nature Structural Biology10, 38 - 44 (2002)
Published online: 9 December 2002; | doi:10.1038/nsb880
There is a Corrigendum (February 2003) associated with this Article.
Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering
Samuel Davis1, Nick Papadopoulos1, Thomas H. Aldrich1, Peter C. Maisonpierre1, Tammy Huang1, Lubomir Kovac1, April Xu1, Raymond Leidich1, Elzbieta Radziejewska1, Ashique Rafique1, Judah Goldberg1, Vivek Jain1, Kevin Bailey1, Margaret Karow1, Jim Fandl1, Steven J. Samuelsson2, Ella Ioffe1, John S. Rudge1, Thomas J. Daly1, Czeslaw Radziejewski1
& George D. Yancopoulos1
1
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
2
Procter and Gamble Pharmaceuticals, P.O. Box 8006, 8700 Mason-Montgomery Road, Mason, Ohio 45040-8006, USA.
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.
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