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: 6.79). 06/2005; 13(5):825-32. DOI: 10.1016/j.str.2005.03.009
Source: PubMed

ABSTRACT 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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    • "Interestingly, our crystal structure of Tie2 bound to Ang2(Barton et al., 2006) and to Ang1 (unpublished data) show that all angiopoietins bind Tie2 in a similar conformation, excluding the possibility of differential Tie2 activation resulting from alternate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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    • "All the angiopoietins are secreted glycoproteins with molecular masses of approximately 70 kDa and similar overall structures, comprising of a secretory leader sequence, coiled coil domain and carboxy-terminal fibrinogen related domain (Davis et al. 1996; Maisonpierre et al. 1997; Valenzuela et al. 1999). It is this C-terminal domain that is responsible for binding of the ligands to their primary receptor Tie2 (Barton et al. 2005; Procopio et al. 1999), a receptor tyrosine kinase expressed almost exclusively in vascular endothelial cells (Dumont et al. 1992; Runting et al. 1993). Interaction of Ang1 or Ang4 with Tie2 stimulates receptor phosphorylation and initiates downstream signalling and functional effects in endothelial cells (Davis et al. 1996; Valenzuela et al. 1999). "
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