Saeb David, Lietzke Emma E, Fuchs Daisy I, Aldrich Emma C, Bruce Kimberley D, Sprenger Kayla G
Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, United States.
Department of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Denver, United States.
Elife. 2025 Sep 10;13:RP102269. doi: 10.7554/eLife.102269.
The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer's disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of human (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in modulating the dynamics of the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the 'Expanded Surface 2,' which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding frequency in the presence of R47H. This suggests that sTREM2's neuroprotective role in AD may, at least in part, arise from the stalk domain's ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD.
髓系细胞触发受体2（TREM2）这种小胶质细胞表面蛋白在介导阿尔茨海默病（AD）中的脑内稳态和炎症反应方面发挥着关键作用。TREM2的可溶性形式（sTREM2）在AD中表现出神经保护作用，但其潜在机制仍不清楚。此外，TREM2和sTREM2之间配体结合的差异对它们在AD病理中的作用具有重要意义，目前仍未得到解释。为了填补这些知识空白，我们进行了迄今为止计算量最大的人类（s）TREM2分子动力学模拟，探究它们与关键的损伤相关和脂蛋白相关磷脂的相互作用以及AD风险突变R47H的影响。我们的结果表明，sTREM2的柔性茎域是sTREM2和TREM2之间差异配体结合的分子基础，这得益于其在调节免疫球蛋白样结构域动力学以及改变典型配体结合位点可及性方面的作用。我们在sTREM2上鉴定出一个新的配体结合位点，称为“扩展表面2”，它是由于茎与免疫球蛋白样结构域的竞争性结合而出现的。此外，我们观察到茎域本身作为配体结合位点发挥作用，在存在R47H的情况下结合频率增加。这表明sTREM2在AD中的神经保护作用可能至少部分源于茎域挽救由AD风险突变导致的功能失调配体结合的能力。最后，我们的研究结果表明，TREM2中R47H诱导的功能障碍可能是由于互补决定区2环运动受限导致配体结合减少以及区分配体的能力受损，从而提出了一种功能丧失的新机制。总之，这些结果为sTREM2在AD病理中的作用提供了有价值的见解，为设计针对AD中（s）TREM2的新治疗方法奠定了基础。
