Solution structure of the cysteine-rich domain in Fn14, a member of the tumor necrosis factor receptor superfamily.
Fn14 is the smallest member of the tumor necrosis factor (TNF) receptor superfamily, and specifically binds to its ligand, TWEAK (TNF-like weak inducer of apoptosis), which is a member of the TNF superfamily. The receptor-ligand recognition between Fn14 and TWEAK induces a variety of cellular processes for tissue remodeling and is also involved in the pathogenesis of some human diseases, such as cancer, chronic autoimmune diseases, and acute ischaemic stroke. The extracellular ligand-binding region of Fn14 is composed of 53 amino acid residues and forms a single, cysteine-rich domain (CRD). In this study, we determined the solution structure of the Fn14 CRD (Glu28-Ala70) by heteronuclear NMR, with a (13)C-/(15)N-labeled sample. The tertiary structure of the CRD comprises a beta-sheet with two strands, followed by a 3(10) helix and a C-terminal alpha-helix, and is stabilized by three disulfide bonds connecting Cys36-Cys49, Cys52-Cys67, and Cys55-Cys64. Comparison of the disulfide bond connectivities and the tertiary structures with those of other CRDs revealed that the Fn14 CRD is similar to the fourth CRD of TNF receptor 1 (A1-C2 module type), but not to the CRD of B-cell maturation antigen and the second CRD of transmembrane activator and CAML (calcium modulator and cyclophilin ligand) interactor (A1-D2 module type). This is the first structural report about the A1-C2 type CRD that could bind to the known target.
He
Fahu
F
RIKEN, Systems and Structural Biology Center, Yokohama, Japan.
Dang
Weirong
W
Saito
Kohei
K
Watanabe
Satoru
S
Kobayashi
Naohiro
N
Güntert
Peter
P
Kigawa
Takanori
T
Tanaka
Akiko
A
Muto
Yutaka
Y
Yokoyama
Shigeyuki
S
D000595:Amino Acid Sequence; D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism; D003627:Data Interpretation, Statistical; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000378:metabolism; D000074050:TWEAK Receptor
D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; D003545:Cysteine