PDBsum entry 4jzc

Signaling protein

PDB id: 4jzc

Contents

Protein chain

218 a.a.

Waters ×189

PDB id:

4jzc

Name:

Signaling protein

Title:

Angiopoietin-2 fibrinogen domain tag mutant

Structure:

Angiopoietin-2. Chain: a. Fragment: fibrinogen-like receptor-binding domain. Synonym: ang-2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: angpt2. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293.

Resolution:

1.90Å R-factor: 0.230 R-free: 0.248

Authors:

X.Yu,T.C.M.Seegar,A.C.Dalton,D.Tzvetkova-Robev,Y.Goldgur,D.B.Nikolov, W.A.Barton

Key ref:

X.Yu et al. (2013). Structural basis for angiopoietin-1-mediated signaling initiation. Proc Natl Acad Sci U S A, 110, 7205-7210. PubMed id: 23592718 DOI: 10.1073/pnas.1216890110

Date:

02-Apr-13 Release date: 08-May-13

Protein chain

O15123  (ANGP2_HUMAN) -  Angiopoietin-2 from Homo sapiens

Seq: 496 a.a.

Struc: 218 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1073/pnas.1216890110

Proc Natl Acad Sci U S A 110:7205-7210 (2013)

PubMed id: 23592718

Structural basis for angiopoietin-1-mediated signaling initiation.

X.Yu, T.C.Seegar, A.C.Dalton, D.Tzvetkova-Robev, Y.Goldgur, K.R.Rajashankar, D.B.Nikolov, W.A.Barton.

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.