The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Department of Medical Genetics, The Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (No.2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
FASEB J. 2024 Feb 29;38(4):e23493. doi: 10.1096/fj.202302387R.
Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease that could cause blindness. It has been established that Norrin forms dimers to activate β-catenin signaling, yet the core interface for Norrin dimerization and the precise mechanism by which Norrin dimerization contributes to the pathogenesis of FEVR remain elusive. Here, we report an NDP variant, c.265T>C (p.Phe89Leu), that interrupted β-catenin signaling by disrupting Norrin dimerization. Structural and functional analysis revealed that the Phe-89 of one Norrin monomer interacts with Pro-98, Ser-101, Arg-121, and Ile-123 of another, forming two core symmetrical dimerization interfaces that are pivotal for the formation of a "hand-by-arm" dimer. Intriguingly, we proved that one of the two core symmetrical interfaces is sufficient for dimerization and activation of β-catenin signaling, with a substantial contribution from the Phe-89/Pro-98 interaction. Further functional analysis revealed that the disruption of both dimeric interfaces eliminates potential binding sites for LRP5, which could be partially restored by over-expression of TSPAN12. In conclusion, our findings unveil a core dimerization interface that regulates Norrin/LRP5 interaction, highlighting the essential role of Norrin dimerization on β-catenin signaling and providing potential therapeutic avenues for the treatment of FEVR.
家族渗出性玻璃体视网膜病变（FEVR）是一种遗传性眼病，可导致失明。现已证实 Norrin 形成二聚体以激活β-连环蛋白信号通路，但 Norrin 二聚化的核心界面以及 Norrin 二聚化促进 FEVR 发病机制的确切机制仍不清楚。在这里，我们报告了一个 NDP 变体 c.265T>C（p.Phe89Leu），该变体通过破坏 Norrin 二聚化来中断β-连环蛋白信号通路。结构和功能分析表明，一个 Norrin 单体的 Phe-89 与另一个 Norrin 单体的 Pro-98、Ser-101、Arg-121 和 Ile-123 相互作用，形成两个核心对称二聚化界面，对于形成“手到臂”二聚体至关重要。有趣的是，我们证明了两个核心对称界面之一足以形成二聚体并激活β-连环蛋白信号通路，其中 Phe-89/Pro-98 相互作用有很大贡献。进一步的功能分析表明，破坏两个二聚体界面消除了 LRP5 的潜在结合位点，而 TSPAN12 的过表达可部分恢复这些结合位点。总之，我们的研究结果揭示了一个调节 Norrin/LRP5 相互作用的核心二聚化界面，突出了 Norrin 二聚化在β-连环蛋白信号通路中的重要作用，并为 FEVR 的治疗提供了潜在的治疗途径。
Mol Genet Genomic Med. 2022-6
Invest Ophthalmol Vis Sci. 2024-3-5
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