title: Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding.
abstract: 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.
authors.affiliation: Center for Integrated Protein Science-CIPSM, Munich, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Lammens
authors.forename: Monika
authors.initials: M
authors.lastname: Baehner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kohnert
authors.forename: Jens
authors.initials: J
authors.lastname: Niewoehner
authors.forename: Leopold
authors.initials: L
authors.lastname: von Proff
authors.forename: Michael
authors.initials: M
authors.lastname: Schraeml
authors.forename: Katja
authors.initials: K
authors.lastname: Lammens
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry*; D003461:Crystallography; D000074049:Cytokine TWEAK; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D048069:Tumor Necrosis Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000074049:Cytokine TWEAK; D007140:Immunoglobulin Fab Fragments; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors