title: Structure of the extracellular domains of human and Xenopus Fn14: implications in the evolution of TWEAK and Fn14 interactions.
abstract: TWEAK (TNF homologue with weak apoptosis-inducing activity) and Fn14 (fibroblast growth factor-inducible protein 14) are members of the tumor necrosis factor (TNF) ligand and receptor super-families. Having observed that Xenopus Fn14 cross-reacts with human TWEAK, despite its relatively low sequence homology to human Fn14, we examined the conservation in tertiary fold and binding interfaces between the two species. Our results, combining NMR solution structure determination, binding assays, extensive site-directed mutagenesis and molecular modeling, reveal that, in addition to the known and previously characterized β-hairpin motif, the helix-loop-helix motif makes an essential contribution to the receptor/ligand binding interface. We further discuss the insight provided by the structural analyses regarding how the cysteine-rich domains of the TNF receptor super-family may have evolved over time.
  
  
  METHODS
  Structural data are available in the Protein Data Bank/BioMagResBank databases under the accession codes 2KMZ, 2KN0 and 2KN1 and 17237, 17247 and 17252.
  TWEAK binds to hFn14 by surface plasmon resonance (View interaction) xeFn14 binds to TWEAK by enzyme linked immunosorbent assay (View interaction) TWEAK binds to xeFn14 by surface plasmon resonance (View interaction) hFn14 binds to TWEAK by enzyme linked immunosorbent assay (View interaction).
authors: Biogen Idec Inc., 14 Cambridge Center, MA, USA.
authors: Maria
authors: M
authors: Pellegrini
authors: Laure
authors: L
authors: Willen
authors: Mai
authors: M
authors: Perroud
authors: Dennis
authors: D
authors: Krushinskie
authors: Kathy
authors: K
authors: Strauch
authors: Hernan
authors: H
authors: Cuervo
authors: Eric S
authors: ES
authors: Day
authors: Pascal
authors: P
authors: Schneider
authors: Timothy S
authors: TS
authors: Zheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000074049:Cytokine TWEAK; D005110:Extracellular Space / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000737:chemistry*; D029867:Xenopus Proteins / Q000737:chemistry*; D014982:Xenopus laevis
chemical_list: D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C581642:TNFRSF12A protein, Xenopus; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D029867:Xenopus Proteins