A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2.

Juan Pablo Prada, Gaby Wangorsch, Kirstin Kucka, Isabell Lang, Thomas Dandekar, Harald Wajant

Bioinformatics (Oxford, England) 2021 May 05

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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. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Juan Pablo Prada, Gaby Wangorsch, Kirstin Kucka, Isabell Lang, Thomas Dandekar, Harald Wajant. A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2. Bioinformatics (Oxford, England). 2021 May 05;37(5):669-676