Bouqdayr Meryem, Abbad Anass, Baba Hanâ, Saih Asmae, Wakrim Lahcen, Kettani Anass
Laboratory of Biology and Health, Faculty of Sciences Ben M'sick, Hassan II University of Casablanca, Casablanca, Morocco.
Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
J Biomol Struct Dyn. 2023;41(23):14179-14196. doi: 10.1080/07391102.2023.2178509. Epub 2023 Feb 10.
CTLA-4 is an immune checkpoint receptor that negatively regulates the T-cell function expressed after T-cell activation to break the immune response. The current study predicted the genomic analysis to explore the functional variations of missense SNPs in the human gene using PolyPhen2, SIFT, PANTHER, PROVEAN, Fathmm, Mutation Assessor, PhD-SNP, SNPs&GO, SNAP2, and MutPred2. Phylogenetic conservation protein was predicted by ConSurf. Protein structural analysis was carried out by I-Mutant3, MUpro, iStable2, PremPS, and ERIS servers. Molecular dynamics trajectory analysis (RMSD, RMSF, Rg, SASA, H-bonds, and PCA) was performed to analyze the dynamic behavior of native and mutant CTLA-4 at the atomic level. Our analysis suggested that C58S, G118R, P137Q, P137R, P137L, P138T, and G146L variants were predicted to be the most deleterious missense variants and highly conserved residues. Moreover, the molecular dynamics analysis proposed a decrease in the protein stability and compactness with the P137R and P138T highlighting the impact of these variants on the function of the CTLA-4 protein.Communicated by Ramaswamy H. Sarma.
CTLA-4是一种免疫检查点受体，可负向调节T细胞激活后表达的T细胞功能，以打破免疫反应。当前研究预测了基因组分析，使用PolyPhen2、SIFT、PANTHER、PROVEAN、Fathmm、Mutation Assessor、PhD-SNP、SNPs&GO、SNAP2和MutPred2来探索人类基因中错义单核苷酸多态性（SNP）的功能变异。通过ConSurf预测系统发育保守蛋白。通过I-Mutant3、MUpro、iStable2、PremPS和ERIS服务器进行蛋白质结构分析。进行分子动力学轨迹分析（均方根偏差、均方根波动、回旋半径、溶剂可及表面积、氢键和主成分分析）以在原子水平分析天然和突变型CTLA-4的动态行为。我们的分析表明，C58S、G118R、P137Q、P137R、P137L、P138T和G146L变异被预测为最有害的错义变异和高度保守残基。此外，分子动力学分析表明，P137R和P138T会导致蛋白质稳定性和紧密性下降，突出了这些变异对CTLA-4蛋白功能的影响。由拉马斯瓦米·H·萨尔马传达。
