{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:10:36Z","timestamp":1773900636561,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T00:00:00Z","timestamp":1601337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["324392634"],"award-info":[{"award-number":["324392634"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR 221"],"award-info":[{"award-number":["TRR 221"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Wa 1025\/21-1"],"award-info":[{"award-number":["Wa 1025\/21-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Da 208\/13-1"],"award-info":[{"award-number":["Da 208\/13-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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\u2013receptor 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\u2013PLAD affinities and different activities of receptor clusters explain the observed differences in the TNF receptor stimulating activities of soluble TNF.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>All scripts and data are in manuscript and supplement at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa844","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T19:17:41Z","timestamp":1600197461000},"page":"669-676","source":"Crossref","is-referenced-by-count":14,"title":["A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2"],"prefix":"10.1093","volume":"37","author":[{"given":"Juan Pablo","family":"Prada","sequence":"first","affiliation":[{"name":"Department of Bioinformatics, Biocenter, University of W\u00fcrzburg , W\u00fcrzburg 97074, Germany"}]},{"given":"Gaby","family":"Wangorsch","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Biocenter, University of W\u00fcrzburg , W\u00fcrzburg 97074, Germany"}]},{"given":"Kirstin","family":"Kucka","sequence":"additional","affiliation":[{"name":"Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital W\u00fcrzburg , W\u00fcrzburg 97080, Germany"}]},{"given":"Isabell","family":"Lang","sequence":"additional","affiliation":[{"name":"Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital W\u00fcrzburg , W\u00fcrzburg 97080, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-7625","authenticated-orcid":false,"given":"Thomas","family":"Dandekar","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Biocenter, University of W\u00fcrzburg , W\u00fcrzburg 97074, Germany"},{"name":"Department of Structural and Computational Biology, European Molecular Biology Laboratory (EMBL) , 69012 Heidelberg, Germany"}]},{"given":"Harald","family":"Wajant","sequence":"additional","affiliation":[{"name":"Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital W\u00fcrzburg , W\u00fcrzburg 97080, Germany"}]}],"member":"286","published-online":{"date-parts":[[2020,9,29]]},"reference":[{"key":"2023051704095532700_btaa844-B2","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/0092-8674(93)90132-A","article-title":"Crystal structure of the soluble human 55 kd TNF receptor-human TNF\u03b2 complex: implications for TNF receptor activation","volume":"73","author":"Banner","year":"1993","journal-title":"Cell"},{"key":"2023051704095532700_btaa844-B3","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.cellsig.2010.02.011","article-title":"Single chain TNF derivatives with individually mutated receptor binding sites reveal differential stoichiometry of ligand receptor complex formation for TNFR1 and TNFR2","volume":"22","author":"Boschert","year":"2010","journal-title":"Cell. 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