Neuronal growth regulator 1 (NEGR1) and neurotrimin (NTM) are abundant cell-surface proteins found in the brain and form part of the IgLON (Immunoglobulin LSAMP, OBCAM, Neurotrimin) family. In humans, NEGR1 is implicated in obesity and mental disorders, while NTM is linked to intelligence and cognitive function. IgLONs dimerize homophilically and heterophilically, and they are thought to shape synaptic connections and neural circuits by acting in trans (spanning cellular junctions) and/or in cis (at the same side of a junction). Here, we reveal homodimeric structures of NEGR1 and NTM. They assemble into V-shaped complexes via their Ig1 domains, and disruption of the Ig1–Ig1 interface abolishes dimerization in solution. A hydrophobic ridge from one Ig1 domain inserts into a hydrophobic pocket from the opposing Ig1 domain producing an interaction interface that is highly conserved among IgLONs but remarkably plastic structurally. Given the high degree of sequence conservation at the interaction interface, we tested whether different IgLONs could elicit the same biological effect in vivo. In a small-scale study administering different soluble IgLONs directly into the brain and monitoring feeding, only NEGR1 altered food intake significantly. Taking NEGR1 as a prototype, our studies thus indicate that while IgLONs share a conserved mode of interaction and are able to bind each other as homomers and heteromers, they are structurally plastic and can exert unique biological action.

神经元生长调节剂 1 (NEGR1) 和神经三元 (NTM) 是在大脑中发现的丰富的细胞表面蛋白，是 IgLON（I免疫球蛋白L SAMP、O BCAM、N eurotrimin）家族的一部分。在人类中，NEGR1 与肥胖和精神障碍有关，而 NTM 与智力和认知功能有关。IgLON 同嗜性和异嗜性二聚化，并且它们被认为通过反式（跨越细胞连接）和/或顺式（在连接的同一侧）作用来形成突触连接和神经回路。在这里，我们揭示了 NEGR1 和 NTM 的同源二聚体结构。它们组装成V形的复合物通过它们的 Ig1 结构域和 Ig1-Ig1 界面的破坏消除了溶液中的二聚化。来自一个 Ig1 结构域的疏水脊插入来自相对 Ig1 结构域的疏水口袋中，产生了一个相互作用界面，该界面在 IgLON 之间高度保守，但在结构上具有显着的可塑性。鉴于相互作用界面的高度序列保守性，我们测试了不同的 IgLON 是否可以在体内引发相同的生物学效应. 在一项将不同的可溶性 IgLON 直接注入大脑并监测进食的小规模研究中，只有 NEGR1 显着改变了食物摄入量。以 NEGR1 为原型，我们的研究因此表明，虽然 IgLON 具有保守的相互作用模式，并且能够作为同聚体和异聚体相互结合，但它们在结构上是可塑性的，可以发挥独特的生物作用。