Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China.
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
J Biomol Struct Dyn. 2022 Oct;40(17):8085-8099. doi: 10.1080/07391102.2021.1907225. Epub 2021 Apr 5.
The synapse is a highly specialized and dynamic structure, which is involved in regulating neurotransmission. Nerve cell adhesion molecule is a kind of transmembrane protein that mediates the interaction between cells and cells, cells and extracellular matrix, and plays a role in cell recognition, metastasis, and transmembrane signal transduction. Among nerve cell adhesion molecules, Neurexins (NRXNs) and Neuroligins (NLGNs) have been focused due to the relation with autism and other neuropsychiatric diseases. The previous research discovered numerous variants in NRXNs and NLGNs reported in neurodevelopmental disorders by genomic sequencing. However, structural variants in synaptic molecules caused by genome variants still prevent us from understanding the molecular mechanism of diseases. Thus, we sought to conduct a comprehensive risk assessment of the known and gene variants by protein structure analysis. In this study, we analyzed the structural properties of the NRXN/NLGN complex by calculating free energy in residue scanning, in combination with existing risk evaluation tools to focus on candidate missense mutations. Our calculations show that five candidate missense mutations in NLGNs can reduce the stability of NLGNs and even prevent the formation of NRXN/NLGN complexes, namely R87W, R204H, R437H, R437C and R583W. In addition, we found that the affinity of the amino acid substitution (Leu593Phe) (ΔΔ) changes the affinity of the NLGN dimer. Overall, we have identified important potential pathological variants that provide clues to biomarkers. Communicated by Ramaswamy H. Sarma.
突触是一种高度特化和动态的结构，参与调节神经递质传递。神经细胞黏附分子是一种跨膜蛋白，介导细胞与细胞、细胞与细胞外基质之间的相互作用，在细胞识别、迁移和跨膜信号转导中发挥作用。在神经细胞黏附分子中，Neurexins（NRXNs）和Neuroligins（NLGNs）由于与自闭症和其他神经精神疾病有关而受到关注。以前的研究通过基因组测序发现了许多在神经发育障碍中报道的 NRXNs 和 NLGNs 的变体。然而，由于基因组变异导致的突触分子结构变异仍然使我们无法了解疾病的分子机制。因此，我们试图通过蛋白质结构分析对已知的和基因变体进行全面的风险评估。在这项研究中，我们通过残基扫描计算自由能来分析 NRXN/NLGN 复合物的结构特性，并结合现有的风险评估工具，重点关注候选错义突变。我们的计算表明，NLGNs 中的五个候选错义突变可以降低 NLGNs 的稳定性，甚至阻止 NRXN/NLGN 复合物的形成，即 R87W、R204H、R437H、R437C 和 R583W。此外，我们发现氨基酸取代（Leu593Phe）（ΔΔ）的亲和力变化会改变 NLGN 二聚体的亲和力。总的来说，我们已经确定了重要的潜在病理变体，为生物标志物提供了线索。由 Ramaswamy H. Sarma 交流。
