Majeed Asifa, Rashid Amir, Helm Birgit
Department of Biochemistry and Molecular Biology, Army Medical College, National University of Medical Sciences, Abid Majeed Road, Rawalpindi, Pakistan.
From the Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, United Kingdom.
Pak J Pharm Sci. 2018 Sep;31(5):1991-1995.
The high-affinity IgE receptor complex plays an essential part in allergic responses and involved in downstream signaling, released inflammatory mediators that cause allergic responses. The transmembrane region of the high-affinity IgE has a conserved motif (LFAVDTGL) where a polar aspartate (D194) is important for the ligand binding. This modeling study proposes novel potential binding sites between high affinity immunoglobulin E receptor α subunit (FcεRIα) and FcRγ and as a consequence, we propose a new model of FcεRIα and FcRγ interaction (T194) which can mediate downstream signaling in allergic response. The docking of FcRγ with wild-type (D194) and mutant human high affinity immunoglobulin E receptor α subunit (D194T, D194I, D194L, D194A, D194V, D194E, D194S and D194R) has been performed on Autodock Vina. This modeling study is based on lab data obtained by carrying out site-directed mutagenesis done at residue D194 of FcεRIα to assess its functional importance for the mediation of intracellular signal cascade. HuFcεRIα D194 residue was replaced with threonine, leucine, serine, arginine, alanine, asparagine and glutamic acid. FcRγ docking on mutated huFcεRIα (D194T) indicated a new site of interaction and emphasizes the significance of the charge and size of an amino acid at position 194 in huFcεRIα subunit. Amino acids D & T at position 194 are important for cell surface localization, interactions, distribution and downstream signaling of IgE receptor subunit. These proposed models may herald in better therapeutic interventions to combat unfavorably allergic diseases.
高亲和力IgE受体复合物在过敏反应中起关键作用，并参与下游信号传导，释放引起过敏反应的炎症介质。高亲和力IgE的跨膜区域有一个保守基序（LFAVDTGL），其中极性天冬氨酸（D194）对配体结合很重要。这项建模研究提出了高亲和力免疫球蛋白E受体α亚基（FcεRIα）和FcRγ之间新的潜在结合位点，因此，我们提出了一种FcεRIα和FcRγ相互作用的新模型（T194），其可介导过敏反应中的下游信号传导。已在Autodock Vina上进行了FcRγ与野生型（D194）和突变型人高亲和力免疫球蛋白E受体α亚基（D194T、D194I、D194L、D194A、D194V、D194E、D194S和D194R）的对接。这项建模研究基于通过对FcεRIα的D194残基进行定点诱变获得的实验室数据，以评估其对介导细胞内信号级联反应的功能重要性。将人FcεRIα的D194残基替换为苏氨酸、亮氨酸、丝氨酸、精氨酸、丙氨酸、天冬酰胺和谷氨酸。FcRγ与突变型人FcεRIα（D194T）的对接表明了一个新的相互作用位点，并强调了人FcεRIα亚基中194位氨基酸的电荷和大小的重要性。194位的天冬氨酸和苏氨酸对IgE受体亚基的细胞表面定位、相互作用、分布和下游信号传导很重要。这些提出的模型可能预示着在对抗不良过敏疾病方面有更好的治疗干预措施。
