1OSX

Solution Structure of the Extracellular Domain of BLyS Receptor 3 (BR3)

Summary for 1OSX

• Entry DOI: 10.2210/pdb1osx/pdb
• Related: 1MPV 1OSG
• NMR Information: BMRB: 5750
• Descriptor: Tumor necrosis factor receptor superfamily member 13C (1 entity in total)
• Functional Keywords: cysteine-rich domain, extracellular domain, tumor necrosis factor receptor, immune system
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type III membrane protein (Probable): Q96RJ3
• Total number of polymer chains: 1
• Total formula weight: 6541.66

Authors

Gordon, N.C.,Pan, B.,Hymowitz, S.G.,Yin, J.P.,Kelley, R.F.,Cochran, A.G.,Yan, M.,Dixit, V.M.,Fairbrother, W.J.,Starovasnik, M.A. (deposition date: 2003-03-20, release date: 2003-05-27, Last modification date: 2024-10-16)

Primary citation

Gordon, N.C.,Pan, B.,Hymowitz, S.G.,Yin, J.P.,Kelley, R.F.,Cochran, A.G.,Yan, M.,Dixit, V.M.,Fairbrother, W.J.,Starovasnik, M.A.
BAFF/BLyS receptor 3 comprises a minimal TNF receptor-like module that encodes a highly focused ligand-binding site
Biochemistry, 42:5977-5983, 2003

PubMed Abstract: BAFF/BLyS, a member of the tumor necrosis family (TNF) superfamily of ligands, is a crucial survival factor for B cells. BAFF binds three receptors, TACI, BCMA, and BR3, with signaling through BR3 being essential for promoting B cell function. Typical TNF receptor (TNFR) family members bind their cognate ligands through interactions with two cysteine-rich domains (CRDs). However, the extracellular domain (ECD) of BR3 consists of only a partial CRD, with cysteine spacing distinct from other modules described previously. Herein, we report the solution structure of the BR3 ECD. A core region of only 19 residues adopts a stable structure in solution. The BR3 fold is analogous to the first half of a canonical TNFR CRD but is stabilized by an additional noncanonical disulfide bond. BAFF-binding determinants were identified by shotgun alanine-scanning mutagenesis of the BR3 ECD expressed on phage. Several of the key BAFF-binding residues are presented from a beta-turn that we have shown previously to be sufficient for ligand binding when transferred to a structured beta-hairpin scaffold [Kayagaki, N., Yan, M., Seshasayee, D., Wang, H., Lee, W., French, D. M., Grewal, I. S., Cochran, A. G., Gordon, N. C., Yin, J., Starovasnik, M. A, and Dixit, V. M. (2002) Immunity 10, 515-524]. Outside of the turn, mutagenesis identifies additional hydrophobic contacts that enhance the BAFF-BR3 interaction. The crystal structure of the minimal hairpin peptide, bhpBR3, in complex with BAFF reveals intimate packing of the six-residue BR3 turn into a cavity on the ligand surface. Thus, BR3 binds BAFF through a highly focused interaction site, unprecedented in the TNFR family.

PubMed: 12755599
DOI: 10.1021/bi034017g

Experimental method

SOLUTION NMR