El Fessikh Meriem, Elkarhat Zouhair, Flatters Delphine, Camproux Anne-Claude, Belghiti Hakim, Guerinech Hassania, Bakri Youssef, Dakka Nadia, El Baghdadi Jamila
Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco.
Laboratory of Human Pathologies Biology, and Genomic Center of Human Pathologies, Faculty of Sciences, Mohammed V University, Rabat, Morocco.
J Biomol Struct Dyn. 2023 Aug-Sep;41(14):6546-6558. doi: 10.1080/07391102.2022.2109755. Epub 2022 Aug 13.
Leptin receptor (LEPR) is a member of the class I cytokine receptor family that receives and transmits leptin signals. It is primarily involved in the regulation of energy expenditure and food intake. This study aimed to evaluate the association of gene polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, with obesity in Moroccan women and to explore the structural and functional consequences of these SNPs. The variants were genotyped using the Sanger sequencing method. The three-dimensional structures of LEPR extracellular domains were determined using a template-based tertiary structure modeling web server and the protein variants were generated using in silico mutagenesis. The amino acids conservation analysis in the variants region was performed based on a protein's evolutionary profile. The molecular dynamics simulations of the wild-types and variants N-terminal, cytokine receptor homology I and fibronectin type III domains of LEPR protein were performed to investigate their impact on the domain structures. We identified that only Lys656Asn polymorphism is associated with obesity in Moroccan women (P = 0.024). In silico analyses revealed that Lys109, Gln223 and Lys656 are exposed residues and their substitution leads to changes in protein structure through loss or gain of hydrogen bonds and hydrophobic interactions. Lys656Asn increases the stability and decreased flexibility of the fibronectin type III domain. Lys109Arg highly decreases the stability and increases flexibility and the overall dimension of N-terminal and cytokine receptor homology I domains. Gln223Arg increases the stability and the compaction level of these domains. These results provide insight into the involvement of variants in obesity development.Communicated by Ramaswamy H. Sarma.
瘦素受体（LEPR）是I类细胞因子受体家族的成员，负责接收和传递瘦素信号。它主要参与能量消耗和食物摄入的调节。本研究旨在评估基因多态性Lys109Arg、Gln223Arg和Lys656Asn与摩洛哥女性肥胖的关联，并探讨这些单核苷酸多态性（SNP）的结构和功能后果。使用桑格测序法对这些变体进行基因分型。利用基于模板的三级结构建模网络服务器确定LEPR细胞外结构域的三维结构，并通过计算机诱变生成蛋白质变体。基于蛋白质的进化谱对变体区域的氨基酸保守性进行分析。对LEPR蛋白的野生型和变体的N端、细胞因子受体同源性I和纤连蛋白III型结构域进行分子动力学模拟，以研究它们对结构域结构的影响。我们发现只有Lys656Asn多态性与摩洛哥女性肥胖有关（P = 0.024）。计算机分析表明，Lys109、Gln223和Lys656是暴露在外的残基，它们的取代会通过氢键和疏水相互作用的丧失或获得导致蛋白质结构的变化。Lys656Asn增加了纤连蛋白III型结构域的稳定性并降低了其灵活性。Lys109Arg显著降低了稳定性，增加了灵活性以及N端和细胞因子受体同源性I结构域的整体尺寸。Gln223Arg增加了这些结构域的稳定性和紧密程度。这些结果为变体在肥胖发展中的作用提供了见解。由拉马斯瓦米·H·萨尔马传达。
