Mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration, including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signaling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterized. Here, we present phage display generated antibody single-chain variable fragments (scFvs) to human TREM2 immunoglobulin-like domain. Co-crystal structures revealed the binding of two scFvs to an epitope on the TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species, which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterization of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.

TREM2 是大脑中小胶质细胞表达的一种受体，其突变与神经退行性疾病（包括阿尔茨海默病）的风险增加有关。大量研究支持 TREM2 在感知破坏性刺激和触发神经保护所需的信号级联中发挥作用。尽管它发挥着重要作用，但 TREM2 激活的配体和调节因子，以及控制 TREM2 依赖性反应及其从膜上裂解的机制，仍然知之甚少。在这里，我们展示了噬菌体展示产生的针对人 TREM2 免疫球蛋白样结构域的抗体单链可变片段 (scFv)。共晶结构揭示了两个 scFv 与推定配体结合位点远端 TREM2 结构域上的表位的结合。在 HEK293 细胞模型中观察到寡聚 scFv 种类的功能活性增强，抑制可溶性 TREM2 的产生。我们希望对其表位和特性的详细表征将有助于使用这些可再生结合剂作为 TREM2 研究的结构和功能生物学工具。