Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding

PLoS One. 2013 May 8;8(5):e62697. doi: 10.1371/journal.pone.0062697. Print 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / chemistry*
  • Crystallography
  • Cytokine TWEAK
  • Humans
  • Immunoglobulin Fab Fragments / chemistry*
  • Immunoglobulin Fab Fragments / metabolism
  • Models, Molecular*
  • Protein Binding
  • Protein Conformation*
  • Tumor Necrosis Factors / chemistry*
  • Tumor Necrosis Factors / metabolism


  • Antibodies, Neutralizing
  • Cytokine TWEAK
  • Immunoglobulin Fab Fragments
  • TNFSF12 protein, human
  • Tumor Necrosis Factors

Grants and funding

KPH is supported by the DFG (Sonderforschungsbereich 684) and the German Excellence Initiative (CIPSM cluster). KPH and KL acknowledge support by the SFB 1054. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.