Unknown

Dataset Information

0

Structural basis for angiopoietin-1-mediated signaling initiation.


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.

SUBMITTER: Yu X 

PROVIDER: S-EPMC3645508 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structural basis for angiopoietin-1-mediated signaling initiation.

Yu Xuehong X   Seegar Tom C M TC   Dalton Annamarie C AC   Tzvetkova-Robev Dorothea D   Goldgur Yehuda Y   Rajashankar Kanagalaghatta R KR   Nikolov Dimitar B DB   Barton William A WA  

Proceedings of the National Academy of Sciences of the United States of America 20130416 18


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 rol  ...[more]

Similar Datasets

| S-EPMC10363478 | biostudies-literature
| S-EPMC3593053 | biostudies-literature
| S-EPMC6590061 | biostudies-literature
2013-07-13 | E-GEOD-48827 | biostudies-arrayexpress
| S-EPMC3465688 | biostudies-literature
| S-EPMC8812562 | biostudies-literature
2013-07-13 | GSE48827 | GEO
| S-EPMC8349879 | biostudies-literature
| S-EPMC6372665 | biostudies-literature
| S-EPMC8752837 | biostudies-literature