Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2–Tie2 complex

Abstract

The Tie receptor tyrosine kinases and their angiopoietin (Ang) ligands play central roles in developmental and tumor-induced angiogenesis. Here we present the crystal structures of the Tie2 ligand-binding region alone and in complex with Ang2. In contrast to prediction, Tie2 contains not two but three immunoglobulin (Ig) domains, which fold together with the three epidermal growth factor domains into a compact, arrowhead-shaped structure. Ang2 binds at the tip of the arrowhead utilizing a lock-and-key mode of ligand recognition—unique for a receptor kinase—where two complementary surfaces interact with each other with no domain rearrangements and little conformational change in either molecule. Ang2-Tie2 recognition is similar to antibody–protein antigen recognition, including the location of the ligand-binding site within the Ig fold. Analysis of the structures and structure-based mutagenesis provide insight into the mechanism of receptor activation and support the hypothesis that all angiopoietins interact with Tie2 in a structurally similar manner.

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Figure 1: Structure of the Tie2 ligand-binding region.
Figure 2: Sequence alignment of the interacting domains of angiopoietins and Ties.
Figure 3: Ligand binding and activation of wild-type and mutant Tie2.
Figure 4: Crystal structure of the Ang2–Tie2 complex.
Figure 5: Structure of the Ang2-Tie2 interface.
Figure 6: A model for Tie2 activation by angiopoietins.

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Acknowledgements

This work was supported by the US National Institutes of Health (RO1-HL077249). We thank the staffs of beamlines X29A at the NSLS and NE-CAT at the Advanced Photon Source. Operation of the NSLS synchrotron beamline is supported by the US Department of Energy (contract no. DE-AC02-98CH10886). NE-CAT synchrotron beamline operations are supported by the National Center for Research Resources at the US National Institutes of Health (award RR-15301).

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Correspondence to Dimitar B Nikolov.

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Supplementary Fig. 1

A representative region of the experimental SAD electron density (PDF 1288 kb)

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Barton, W., Tzvetkova-Robev, D., Miranda, E. et al. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2–Tie2 complex. Nat Struct Mol Biol 13, 524–532 (2006). https://doi.org/10.1038/nsmb1101

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