Angiopoietins have distinct modular domains essential for receptor binding,dimerization and superclustering |
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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 |
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Institution: | Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA. samuel.davis@regeneron.com |
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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. |
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