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Gyunghee, Jo
단백질 커뮤니케이션 그룹
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Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody

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Title
Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody
Author(s)
Gyunghee Jo; Jeomil Bae; Ho Jeong Hong; Ah-reum Han; Do-Kyun Kim; Seon Pyo Hong; Kim, Jung A; Sangkyu Lee; Gou Young Koh; Ho Min Kim
Publication Date
2021-11-01
Journal
Nature Communications, v.12, no.1
Publisher
Nature Research
Abstract
© 2021, The Author(s).Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application.
URI
https://pr.ibs.re.kr/handle/8788114/11019
DOI
10.1038/s41467-021-26620-1
ISSN
2041-1723
Appears in Collections:
Pioneer Research Center for Biomolecular and Cellular Structure(바이오분자 및 세포구조 연구단) > Protein Communication Group(단백질 커뮤니케이션 그룹) > 1. Journal Papers (저널논문)
Center for Vascular Research(혈관 연구단) > 1. Journal Papers (저널논문)
Center for Cognition and Sociality(인지 및 사회성 연구단) > 1. Journal Papers (저널논문)
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