Structure of the Angiopoietin-2 Receptor Binding Domain and Identification of Surfaces Involved in Tie2 Recognition

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Structure (Impact Factor: 5.62). 06/2005; 13(5):825-32. DOI: 10.1016/j.str.2005.03.009
Source: PubMed


The angiopoietins comprise a small class of secreted glycoproteins that play crucial roles in the maturation and maintenance of the mammalian vascular and lymphatic systems. They exert their effects through a member of the tyrosine kinase receptor family, Tie2. Angiopoietin/Tie2 signaling is unique among tyrosine kinase receptor-ligand systems in that distinct angiopoietin ligands, although highly homologous, can function as agonists or antagonists in a context-dependent manner. In an effort to understand this molecular dichotomy, we have crystallized and determined the 2.4 A crystal structure of the Angiopoietin-2 (Ang2) receptor binding region. The structure reveals a fibrinogen fold with a unique C-terminal P domain. Conservation analysis and structure-based mutagenesis identify a groove on the Ang2 molecular surface that mediates receptor recognition.

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    • "Ang1 and Ang2 share approximately 60% homology in their amino acid sequence, as well as a common protein structure consisting of an amino terminal that modulates super-clustering, a coiled-coil domain for the formation of homodimers and a fibrinogen-like domain with ligand activity [16, 40, 132]. Ang1 and Ang2 bind to the same domain on Tie2 with similar affinities [15, 16, 132] and conformation [49]. However, they have opposite effects on receptor phosphorylation and activation. "
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    • "Interestingly, our crystal structure of Tie2 bound to Ang2(Barton et al., 2006) and to Ang1 (unpublished data) show that all angiopoietins bind Tie2 in a similar conformation, excluding the possibility of differential Tie2 activation resulting from alternate Tie2/angiopoietin structural arrangements. However, our structural analysis does suggest that the different angiopoietin ligands could present distinct molecular surfaces outside of the receptor-binding interface that could influence the Tie1-Tie2 receptor complexes(Barton et al., 2005). Based upon our findings we hypothesized that the observed direct Tie2/Tie1 interactions are inhibitory and the ability, or inability, of individual angiopoietins to effectively destabilize the Tie1/Tie2 complexes at the cell surface would define their respective agonistic or antagonistic roles. "
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    • "The P-domain mediates interaction of FReD containing proteins such as fibrinogen and tachylectin 5A with their ligands and it is this region of the Ang FReD that interacts with Tie2 [9]. The structure of Ang2 bound to Tie2 ectodomain has been solved and shows the Ang2 P-domain interacting with the second Ig domain of the receptor which is within a globular fold containing three Ig and three EGF-like domains at the amino-terminal head of the receptor [9–11]. Comparison of un-liganded and Ang2-bound Tie2 ectodomain suggests no significant conformational change in Tie2 on ligand binding [10]. "
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