Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding.
The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3648529?pdf=render |
| _version_ | 1819059011748626432 |
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| author | Alfred Lammens Monika Baehner Ulrich Kohnert Jens Niewoehner Leopold von Proff Michael Schraeml Katja Lammens Karl-Peter Hopfner |
| author_facet | Alfred Lammens Monika Baehner Ulrich Kohnert Jens Niewoehner Leopold von Proff Michael Schraeml Katja Lammens Karl-Peter Hopfner |
| author_sort | Alfred Lammens |
| collection | DOAJ |
| description | The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases. |
| first_indexed | 2024-12-21T14:04:19Z |
| format | Article |
| id | doaj.art-b1a43aebdf8f49f2bbe2a88a81a89869 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T14:04:19Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b1a43aebdf8f49f2bbe2a88a81a898692022-12-21T19:01:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0185e6269710.1371/journal.pone.0062697Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding.Alfred LammensMonika BaehnerUlrich KohnertJens NiewoehnerLeopold von ProffMichael SchraemlKatja LammensKarl-Peter HopfnerThe tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases.http://europepmc.org/articles/PMC3648529?pdf=render |
| spellingShingle | Alfred Lammens Monika Baehner Ulrich Kohnert Jens Niewoehner Leopold von Proff Michael Schraeml Katja Lammens Karl-Peter Hopfner Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. PLoS ONE |
| title | Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. |
| title_full | Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. |
| title_fullStr | Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. |
| title_full_unstemmed | Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. |
| title_short | Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. |
| title_sort | crystal structure of human tweak in complex with the fab fragment of a neutralizing antibody reveals insights into receptor binding |
| url | http://europepmc.org/articles/PMC3648529?pdf=render |
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