Bioinformatics Division, ICMR-Regional Medical Research Centre, Nalco Square, Chandrasekharpur, Bhubaneswar, 751023, Odisha, India.
Mycology Laboratory, ICMR-Regional Medical Research Centre, Nalco Square, Chandrasekharpur, Bhubaneswar, 751023, Odisha, India.
J Mol Model. 2023 Nov 4;29(11):360. doi: 10.1007/s00894-023-05770-7.
The specialised family of triggering receptors expressed on myeloid cells (TREMs) plays a pivotal role in causing neurodegenerative disorders and activating microglial anti-inflammatory responses. Nasu-Hakola disease (NHD), a rare autosomal recessive disorder, has been associated with mutations in TREM2, which is also responsible for raising the risk of Alzheimer's disease (AD). Herein, we have made an endeavour to differentiate the confirmed pathogenic variants in TREM2 extra-cellular domain (ECD) linked with NHD and AD using mutation-induced fold stability change (∆∆G), with the computation of 12distinct structure-based methods through saturation mutagenesis. Correlation analysis between relative solvent accessibility (RSA) and ∆∆G expresses the discrete distributive behaviour of mutants associated with TREM2 in AD (R = 0.061) and NHD (R = 0.601). Our findings put an emphasis on W50 and V126 as major players in maintaining V-like domain in TREM2. Interestingly, we discern that both of them interact with a common residue Y108, which is dissolved upon mutation. This Y108 could have structural or functional role for TREM2 which can be an ideal candidate for further study. Furthermore, the residual interaction network highlights the importance of R47 and R62 in maintaining the CDR loops that are crucial for ligand binding. Future studies using biophysical characterisation of ligand interactions in TREM2-ECD would be helpful for the development of novel therapeutics for AD and NHD.
ConSurf algorithm and ENDscript were used to determine the position and conservation of each residue in the wild-type ECD of TREM2. The mutation-induced fold stability change (∆∆G) of confirmed pathogenic mutants associated with NHD and AD was estimated using 12 state-of-the-art structure-based protein stability tools. Furthermore, we also computed the effect of random mutation on these sites using computational saturation mutagenesis. Linear regression analysis was performed using mutants ∆∆G and RSA through GraphPad software. In addition, a comprehensive non-bonded residual interaction network (RIN) of wild type and its mutants of TREM2-ECD was enumerated using RING3.0.
触发髓系细胞表达的受体（TREMs）家族在引起神经退行性疾病和激活小胶质细胞抗炎反应方面发挥着关键作用。Nasu-Hakola 病（NHD）是一种罕见的常染色体隐性遗传病，与 TREM2 突变有关，TREM2 突变也会增加阿尔茨海默病（AD）的风险。在此，我们通过突变诱导的折叠稳定性变化（∆∆G），使用 12 种不同的基于结构的方法，通过饱和诱变计算，尝试区分与 NHD 和 AD 相关的 TREM2 细胞外结构域（ECD）中的确认致病性变异。相对溶剂可及性（RSA）与 ∆∆G 之间的相关分析表明，与 TREM2 相关的 AD（R = 0.061）和 NHD（R = 0.601）突变体具有离散分布的行为。我们的研究结果强调了 W50 和 V126 作为维持 TREM2 中 V 样结构域的主要因素。有趣的是，我们发现它们都与一个共同的残基 Y108 相互作用，而 Y108 在突变时会溶解。Y108 可能对 TREM2 具有结构或功能作用，这可能是进一步研究的理想候选者。此外，残留的相互作用网络突出了 R47 和 R62 在维持配体结合关键 CDR 环中的重要性。使用 TREM2-ECD 中配体相互作用的生物物理特性研究将有助于开发用于 AD 和 NHD 的新型治疗方法。
使用 Consurf 算法和 ENDscript 确定野生型 TREM2 ECD 中每个残基的位置和保守性。使用 12 种最先进的基于结构的蛋白质稳定性工具估计与 NHD 和 AD 相关的确认致病性突变的突变诱导折叠稳定性变化（∆∆G）。此外，我们还使用计算饱和诱变计算了这些位点的随机突变的影响。使用 GraphPad 软件通过线性回归分析对 TREM2-ECD 中的突变体 ∆∆G 和 RSA 进行分析。此外，使用 RING3.0 枚举了野生型和突变型 TREM2-ECD 的综合非键残余相互作用网络（RIN）。
