SVEP1 介导 ANG2 与 TIE1 受体结合并驱动下游信号
SVEP1 enables efficient binding of angiopoietin-2 to the TIE1 receptor, allowing receptor phosphorylation and downstream signaling
基于 AlphaFold-multimer 对 SVEP1 复合物的结构预测，蛋白结合实验显示人 CCP20 结构域是 TIE1 的主要结合位点。SVEP1 能介导 ANG2 与 TIE1 的强结合，用 SVEP1 与 ANG2 联合刺激 hdLECs 可引起 TIE1 磷酸化。SVEP1 与 ANG2 激活 TIE1 后启动下游信号，相比单独使用 SVEP1 或 ANG2，进一步促进 FOXO1 核输出和 AKT 磷酸化。作者提出模型：ANG1/2 二聚体同时结合 SVEP1 与 TIE1，将多个 TIE1 受体分子招募到细胞膜上的多聚复合物中，可能放大其信号能力。
来源：eLife · doi.org
The molecular mechanisms that drive (lymph-)angiogenesis are crucial to understanding diseases, such as lymphedema, that are caused due to malformations of the lymphatic vasculature. Recently, an interaction between the secreted protein Svep1, a key regulator in lymphangiogenesis, and the transmembrane receptor Tie1 was shown in zebrafish, humans, and mice. Here, guided by in silico AlphaFold-multimer structure predictions of SVEP1 complexes, we assert with protein binding studies that the human CCP20 domain is the primary binding site for TIE1. We further demonstrate that SVEP1 mediates strong binding of ANG2 and TIE1, and that combined stimulation of hdLECs with SVEP1 and ANG2 leads to phosphorylation of TIE1. TIE1 activation by SVEP1 and ANG2 enables downstream signaling and, in turn, potentiates nuclear exclusion of FOXO1 and phosphorylation of AKT compared to SVEP1 or ANG2 alone. We present a model in which ANG1/2 dimers bind to both SVEP1 and TIE1, resulting in the recruitment of multiple TIE1 receptor molecules to a multimeric complex at the cell membrane, potentially amplifying its signaling capacity.