Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
Int J Mol Sci. 2024 Sep 6;25(17):9667. doi: 10.3390/ijms25179667.
Alzheimer's disease is the most common form of dementia, characterized by the pathological accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized as playing a central role in Aβ clearance and microglia activation in AD. The gene transcriptional product is alternatively spliced to produce three different protein isoforms. The canonical TREM2 isoform binds to DAP12 to activate downstream pathways. However, little is known about the function or interaction partners of the alternative TREM2 isoforms. The present study utilized a computational approach in a systematic search for new interaction partners of the TREM2 isoforms by integrating several state-of-the-art structural bioinformatics tools from initial large-scale screening to one-on-one corroborative modeling and eventual all-atom visualization. CD9, a cell surface glycoprotein involved in cell-cell adhesion and migration, was identified as a new interaction partner for two TREM2 isoforms, and CALM, a calcium-binding protein involved in calcium signaling, was identified as an interaction partner for a third TREM2 isoform, highlighting the potential role of cell adhesion and calcium regulation in AD.
阿尔茨海默病是最常见的痴呆症形式，其特征是淀粉样蛋白-β (Aβ) 斑块和 tau 神经原纤维缠结的病理性积累。髓样细胞表达的触发受体 2 (TREM2) 越来越被认为在 AD 中发挥清除 Aβ 和激活小胶质细胞的核心作用。该基因的转录产物经过选择性剪接产生三种不同的蛋白异构体。经典的 TREM2 异构体与 DAP12 结合以激活下游途径。然而，关于替代 TREM2 异构体的功能或相互作用伙伴知之甚少。本研究通过整合几种最先进的结构生物信息学工具，从初始的大规模筛选到一对一的相互确证建模，最终进行全原子可视化，利用计算方法系统地搜索 TREM2 异构体的新相互作用伙伴。CD9 是一种参与细胞间黏附与迁移的细胞表面糖蛋白，被鉴定为两种 TREM2 异构体的新相互作用伙伴，而 CALM 是一种参与钙信号的钙结合蛋白，被鉴定为第三种 TREM2 异构体的相互作用伙伴，突出了细胞黏附和钙调节在 AD 中的潜在作用。
