%0 Journal Article %1 Berg2007 %A Berg, D. %A Lehne, M. %A Müller, N. %A Siegmund, D. %A Münkel, S. %A Sebald, W. %A Pfizenmaier, K. %A Wajant, H. %D 2007 %J Cell Death and Differentiation %K 2007 izi pfizenmaier %N 12 %P 2021--2034 %R 10.1038/sj.cdd.4402213 %T Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L %U https://www.ncbi.nlm.nih.gov/pubmed/17703232 %V 14 %X Variants of human TRAIL (hTRAIL) and human CD95L (hCD95L), encompassing the TNF homology domain (THD), interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross-linking. The murine counterparts (mTRAIL, mCD95L) showed no or only low receptor binding and were inactive/poorly active after cross-linking. The stalk region preceding the THD of mCD95L conferred secondary aggregation and restored CD95 activation in the absence of cross-linking. A corresponding variant of mTRAIL, however, was still not able to activate TRAIL death receptors, but gained good activity after cross-linking. Notably, disulfide-bonded fusion proteins of the THD of mTRAIL and mCD95L with a subdomain of the tenascin-C (TNC) oligomerization domain, which still assembled into trimers, efficiently interacted with their cognate cellular receptors and robustly stimulated CD95 and TRAILR2 signaling after secondary cross-linking. Introduction of the TNC domain also further enhanced the activity of THD encompassing variants of hTRAIL and hCD95L. Thus, spatial fixation of the N-terminus of the THD appears necessary in some TNF ligands to ensure proper receptor binding. This points to yet unanticipated functions of the stalk and/or transmembrane region of TNF ligands for the functionality of these molecules and offers a broadly applicable option to generate recombinant soluble ligands of the TNF family with superior activity. %Z Berg, DLehne, MMuller, NSiegmund, DMunkel, SSebald, WPfizenmaier, KWajant, HengResearch Support, Non-U.S. Gov'tEnglandCell Death Differ. 2007 Dec;14(12):2021-34. doi: 10.1038/sj.cdd.4402213. Epub 2007 Aug 17. %7 2007/08/19 %@ 1350-9047

@article{Berg2007, abstract = {Variants of human TRAIL (hTRAIL) and human CD95L (hCD95L), encompassing the TNF homology domain (THD), interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross-linking. The murine counterparts (mTRAIL, mCD95L) showed no or only low receptor binding and were inactive/poorly active after cross-linking. The stalk region preceding the THD of mCD95L conferred secondary aggregation and restored CD95 activation in the absence of cross-linking. A corresponding variant of mTRAIL, however, was still not able to activate TRAIL death receptors, but gained good activity after cross-linking. Notably, disulfide-bonded fusion proteins of the THD of mTRAIL and mCD95L with a subdomain of the tenascin-C (TNC) oligomerization domain, which still assembled into trimers, efficiently interacted with their cognate cellular receptors and robustly stimulated CD95 and TRAILR2 signaling after secondary cross-linking. Introduction of the TNC domain also further enhanced the activity of THD encompassing variants of hTRAIL and hCD95L. Thus, spatial fixation of the N-terminus of the THD appears necessary in some TNF ligands to ensure proper receptor binding. This points to yet unanticipated functions of the stalk and/or transmembrane region of TNF ligands for the functionality of these molecules and offers a broadly applicable option to generate recombinant soluble ligands of the TNF family with superior activity.}, added-at = {2023-06-29T13:07:55.000+0200}, annote = {Berg, DLehne, MMuller, NSiegmund, DMunkel, SSebald, WPfizenmaier, KWajant, HengResearch Support, Non-U.S. Gov'tEnglandCell Death Differ. 2007 Dec;14(12):2021-34. doi: 10.1038/sj.cdd.4402213. Epub 2007 Aug 17.}, author = {Berg, D. and Lehne, M. and M{\"{u}}ller, N. and Siegmund, D. and M{\"{u}}nkel, S. and Sebald, W. and Pfizenmaier, K. and Wajant, H.}, biburl = {https://puma.ub.uni-stuttgart.de/bibtex/27d2b8f98400afae3b13cdb620137d949/fabian}, doi = {10.1038/sj.cdd.4402213}, edition = {2007/08/19}, interhash = {480a08206d600534b7779157eea446bb}, intrahash = {7d2b8f98400afae3b13cdb620137d949}, isbn = {1350-9047}, issn = {13509047}, journal = {Cell Death and Differentiation}, keywords = {2007 izi pfizenmaier}, number = 12, pages = {2021--2034}, pmid = {17703232}, timestamp = {2023-06-29T13:07:55.000+0200}, title = {{Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L}}, url = {https://www.ncbi.nlm.nih.gov/pubmed/17703232}, volume = 14, year = 2007 }