Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg 97074, Germany.
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg 97080, Germany.
Bioinformatics. 2021 May 5;37(5):669-676. doi: 10.1093/bioinformatics/btaa844.
Clustering enables TNF receptors to stimulate intracellular signaling. The differential soluble ligand-induced clustering behavior of TNF receptor 1 (TNFR1) and TNFR2 was modeled. A structured, rule-based model implemented ligand-independent pre-ligand binding assembly domain (PLAD)-mediated homotypic low affinity interactions of unliganded and liganded TNF receptors.
Soluble TNF initiates TNFR1 signaling but not TNFR2 signaling despite receptor binding unless it is secondarily oligomerized. We consider high affinity binding of TNF to signaling-incompetent pre-assembled dimeric TNFR1 and TNFR2 molecules and secondary clustering of liganded dimers to signaling competent ligand-receptor clusters. Published receptor numbers, affinities and measured different activities of clustered receptors validated model simulations for a large range of receptor and ligand concentrations. Different PLAD-PLAD affinities and different activities of receptor clusters explain the observed differences in the TNF receptor stimulating activities of soluble TNF.
All scripts and data are in manuscript and supplement at Bioinformatics online.
Supplementary data are available at Bioinformatics online.
聚类使 TNF 受体能够刺激细胞内信号转导。对 TNF 受体 1（TNFR1）和 TNFR2 的差异可溶性配体诱导的聚类行为进行了建模。一种基于结构的、基于规则的模型实现了无配体和配体 TNF 受体的配体非依赖性预配体结合组装域（PLAD）介导的同源低亲和力相互作用。
尽管 TNF 受体结合，但可溶性 TNF 仅起始 TNFR1 信号转导而不起始 TNFR2 信号转导，除非其被次级寡聚化。我们考虑 TNF 与信号失活的预组装二聚体 TNFR1 和 TNFR2 分子的高亲和力结合，以及配体二聚体的次级聚集到信号有效配体-受体簇。已发表的受体数量、亲和力和测定的聚集受体的不同活性验证了模型模拟在很大的受体和配体浓度范围内的有效性。不同的 PLAD-PLAD 亲和力和受体簇的不同活性解释了可溶性 TNF 对 TNF 受体刺激活性的观察到的差异。
所有脚本和数据都在 Bioinformatics 在线的手稿和补充材料中。
补充数据可在 Bioinformatics 在线获得。
