4K0V

Structural basis for angiopoietin-1 mediated signaling initiation

Summary for 4K0V

• Entry DOI: 10.2210/pdb4k0v/pdb
• Descriptor: TEK tyrosine kinase variant, Angiopoietin-1 (2 entities in total)
• Functional Keywords: cellular signaling, tie receptor tyrosine kinase, signaling protein-transferase complex, signaling protein/transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: Q15389
• Total number of polymer chains: 2
• Total formula weight: 85210.04

Authors

Yu, X.,Seegar, T.C.M.,Dalton, A.C.,Tzvetkova-Robev, D.,Goldgur, Y.,Nikolov, D.B.,Barton, W.A. (deposition date: 2013-04-04, release date: 2013-05-08, Last modification date: 2024-11-06)

Primary citation

Yu, X.,Seegar, T.C.,Dalton, A.C.,Tzvetkova-Robev, D.,Goldgur, Y.,Rajashankar, K.R.,Nikolov, D.B.,Barton, W.A.
Structural basis for angiopoietin-1-mediated signaling initiation.
Proc.Natl.Acad.Sci.USA, 110:7205-7210, 2013

PubMed Abstract: Angiogenesis is a complex cellular process involving multiple regulatory growth factors and growth factor receptors. Among them, the ligands for the endothelial-specific tunica intima endothelial receptor tyrosine kinase 2 (Tie2) receptor kinase, angiopoietin-1 (Ang1) and Ang2, play essential roles in balancing vessel stability and regression during both developmental and tumor-induced angiogenesis. Despite possessing a high degree of sequence identity, Ang1 and Ang2 have distinct functional roles and cell-signaling characteristics. Here, we present the crystal structures of Ang1 both unbound and in complex with the Tie2 ectodomain. Comparison of the Ang1-containing structures with their Ang2-containing counterparts provide insight into the mechanism of receptor activation and reveal molecular surfaces important for interactions with Tie2 coreceptors and associated signaling proteins. Using structure-based mutagenesis, we identify a loop within the angiopoietin P domain, adjacent to the receptor-binding interface, which confers the specific agonist/antagonist properties of the molecule. We demonstrate using cell-based assays that an Ang2 chimera containing the Ang1 loop sequence behaves functionally similarly to Ang1 as a constitutive Tie2 agonist, able to efficiently dissociate the inhibitory Tie1/Tie2 complex and elicit Tie2 clustering and downstream signaling.

PubMed: 23592718
DOI: 10.1073/pnas.1216890110

Experimental method

X-RAY DIFFRACTION (4.51 Å)