 |
PDBsum entry 4jzc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Signaling protein
|
PDB id
|
|
|
|
4jzc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for angiopoietin-1-Mediated signaling initiation.
|
|
|
Authors
|
|
X.Yu,
T.C.Seegar,
A.C.Dalton,
D.Tzvetkova-Robev,
Y.Goldgur,
K.R.Rajashankar,
D.B.Nikolov,
W.A.Barton.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2013,
110,
7205-7210.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
