Pillai Joshua, Sung Kijung, Shi Linda, Wu Chengbiao
School of Biological Sciences, University of California, San Diego, 9301 S Scholars Dr, La Jolla, CA 92093, USA.
Department of Neurosciences, University of California San Diego, Medical Teaching Facility, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA.
Comput Struct Biotechnol J. 2025 Jul 4;27:2990-3004. doi: 10.1016/j.csbj.2025.07.003. eCollection 2025.
Triggering receptor expressed on myeloid cells 2 (TREM2), an immune receptor expressed on the surface of microglia, has been identified through genome-wide association studies to be one of the risk factors in Alzheimer's disease (AD). Several studies have also identified missense variants of TREM2 to be associated with frontotemporal dementia and Nasu-Hakola disease (NHD). To date, 51 novel missense variants of TREM2 have been identified in the literature, with the disease risk profiles of most variants still unknown. Assessing and classifying the pathogenicity of these variants is essential to investigate the disease mechanisms and develop effective treatments. Herein, we classified 44 missense variants involved in TREM2 using structural bioinformatic data with AlphaFold2. Using the protocol described in our previous work [1], we determined the structural, stability, and potential functional effects of these variants. Our evaluations of the mutations were divided into those (i) implicated in NHD, (ii) located on the transmembrane domain, (iii) surface of the IgV-like domain, (iv) buried in the receptor, and (v) on low confidence predicted local distance difference test residues. Our analysis of variants involved in NHD suggests that, while V126G imposes the greatest effects, the T66M variant exerts significantly less effects on the TREM2 structures compared to the other remaining variants. Variants in the transmembrane domain of TREM2 did not impose significant alterations to the three-dimensional structure. Outside of known variants in the IgV-like domain, we identified 10 variants that imposed significant destabilizing effects to the structure and are of potential interest. Overall, the baseline biochemical data provided from this study may be informative to experimental efforts to better classify rare coding variants of TREM2 that are of unknown biological and clinical significance.
髓系细胞触发受体2（TREM2）是一种在小胶质细胞表面表达的免疫受体，通过全基因组关联研究已确定其为阿尔茨海默病（AD）的风险因素之一。多项研究还发现TREM2的错义变异与额颞叶痴呆和纳苏-哈科拉病（NHD）相关。迄今为止，文献中已鉴定出51种新的TREM2错义变异，大多数变异的疾病风险特征仍不清楚。评估和分类这些变异的致病性对于研究疾病机制和开发有效治疗方法至关重要。在此，我们使用AlphaFold2的结构生物信息学数据对44种涉及TREM2的错义变异进行了分类。使用我们之前工作[1]中描述的方案，我们确定了这些变异的结构、稳定性和潜在功能影响。我们对突变的评估分为以下几类：（i）与NHD相关的；（ii）位于跨膜结构域的；（iii）IgV样结构域表面的；（iv）埋在受体中的；（v）低置信度预测局部距离差异测试残基上的。我们对与NHD相关变异的分析表明，虽然V126G的影响最大，但与其他剩余变异相比，T66M变异对TREM2结构的影响要小得多。TREM2跨膜结构域中的变异对三维结构没有产生显著改变。在IgV样结构域的已知变异之外，我们鉴定出10种对结构有显著去稳定化作用且具有潜在研究价值的变异。总体而言，本研究提供的基线生化数据可能有助于实验研究，以便更好地分类具有未知生物学和临床意义的TREM2罕见编码变异。
