Norrin信号复合物的结构及结构指导的替代物设计
Architecture of the Norrin signaling complex and structure-guided surrogate design.
文献信息
| PMID | 42907587 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Qinli Hu |
| 作者单位 | Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. |
| 期刊 | Nature structural & molecular biology |
| SCI 分区 | Q1 |
| IF | 11.3 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
Norrin结合Frizzled 4（FZD4）、四跨膜蛋白12（TSPAN12）和低密度脂蛋白受体相关蛋白5（LRP5），以调控血管生成以及血脑屏障和内层血视网膜屏障（BRB）的完整性。Norrin信号异常可导致视网膜病变、BRB缺陷和耳聋。Norrin的治疗性模拟物目前正处于眼科疾病的临床试验中。为表征Norrin信号生物发生的机制，我们使用一种从头设计的FZD4结合物作为“蛋白胶”，测定了Norrin-FZD4-TSPAN12-LRP5信号复合物的结构。我们的结构显示，两个弯曲的Norrin同源二聚体桥接两个FZD4-TSPAN12异源二聚体。LRP5LA3同时与TSPAN12和两个Norrin同源二聚体相互作用，使胞质内的FZD4和LRP5尾部定位以激活信号。基于我们的发现，我们设计了作为Norrin替代物的FZD4CRD-LRP5LA3双特异性结合物。我们的信号实验表明，Norrin替代物的寡聚化增强了信号效力。因此，这项工作揭示了Norrin信号是如何产生的，并可能有助于Norrin/Wnt模拟物的开发。
英文摘要
Norrin binds Frizzled 4 (FZD4), tetraspanin 12 (TSPAN12) and low-density lipoprotein receptor-related protein 5 (LRP5) to regulate angiogenesis and the integrity of the blood-brain barrier and inner blood-retina barrier (BRB). Aberrant Norrin signal causes retinopathies, BRB defects and deafness. Therapeutic mimetics of Norrin are currently in clinical trials for eye diseases. To characterize the mechanism of Norrin signal biogenesis, we determined the structure of a Norrin-FZD4-TSPAN12-LRP5 signaling complex using a de novo designed FZD4 binder as a 'protein glue'. Our structure shows that two curved Norrin homodimers bridge two FZD4-TSPAN12 heterodimers. LRP5LA3 simultaneously interacts with TSPAN12 and two Norrin homodimers, positioning the cytosolic FZD4 and LRP5 tails for signal activation. On the basis of our findings, we designed FZD4CRD-LRP5LA3 bispecific binders that act as Norrin surrogates. Our signaling assays showed that oligomerization of the Norrin surrogate enhances signaling potency. Thus, this work reveals how the Norrin signal is generated and may assist in the development of Norrin/Wnt mimetics.