Tie2 receptor ectodomain complexed with Ang2
A blood vessel is built through two processes called angiopoiesis and neoangiogenesis. The first process, angiopoiesis, is a process in which endothelial cells of blood vessel are stabilized by the support of parietal cells. However, if oxygen becomes locally scarce, parietal cells separate, and blood vessel branches off and extended to the local part where oxygen is needed. This process is called neoangiogenesis. If nutrition and oxygen become sufficient at the local part, parietal cells accumulates to endothelial cells again, and the new blood vessel is stabilized.
The Tie2 receptor tyrosine kinase of endothelial cells is involved in binding and release of parietal cells.
In the normal oxygen state, Ang1 (angiopoietin-1, neoangiogenesis activating factor) from parietal cell bind with Tie2. Then, Tie2 is activated, and mediates that parietal cell bind to endothelial cell.
To the contrary, in the low oxygen state, Ang2 (angiopoietin-2), an antagonist of Ang1, is secreted from endothelial cells. Upon binding with Ang2, Tie2 turns to its active state, and parietal cells separates from the endothelial cells. That is, Tie2 behaves as the switch for the two processes.
However, if Ang2 is secreted constantly, the activity of Tie2 is inhibited indefinitely, and unstable new blood vessel without the support of parietal cells continues to form. It is thought that this causes a tumor. It is reported that administration of soluble Tie2 ectodomain reduces vascular length and tumor growth in vivo. Thus, Tie2 may be used as a tumor removal agent.
Tie2 is the transmembrane protein belonging to RTKs superfamily. (Fig.1). The ectodomain (i.e., extracellular part) of Tie2 consist of three Ig (immunoglobulin) domains, three EGF (epidermal growth factor) domains, and a FNIII (fibronectin type III). Ang2, the ligand of Tie2, contains an N-terminus part that modulates angiopoietin clustering (superclustering region), followed by a coiled-coil motif and a fibrinogen-like region at the C-terminus. The structure shown here is a complex of the receptor region (23-445) of Tie2, and C-terminus of Ang2 (residues 280-495) (Fig. 2). Tie2 receptor region contains three Ig domains which fold together with the three EGF into a compact, arrowhead-shaped structure. Ang2 binds at the tip of the arrowhead (Ig2 region). This structure is stabilized by fourteen disulfide bonds (one each is present in Ig1 and Ig3, and four in each of the EGF). Although all of the three Ig domains are classified into the so-called I class, each of them differs delicately (*1). There is little conformational change in either molecule after binding. Nevertheless, in the direction of Tie2, C'-strand of Ig2 is shifted by 1.0-2.6A toward incoming Ang2 (Fig.3). This enables His163 of C'-strand to make van der Waals contacts with the surface loop of Ang2. In the direction of Ang2, Ser480 shifts slightly to make a hydrogen bond with a hydroxyl group of the Ig2 domain.
(*1) The immunoglobulin is classified into four classes(V, C1, C2, I) according to the feature of the structure.
Protein Data Bank (PDB)
Barton, W.A. Tzvetkova-Robev, D. Miranda, E.P. Kolev, M.V. Rajashankar, K.R. Himanen, J.P. Nikolov, D.B.; "Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex."; Nat.Struct.Mol.Biol.; (2006) 13:524-532 PubMed:16732286.
author: Jun-ichi Ito