Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes

J Mol Biol. 2002 Feb 1;315(5):1145-54. doi: 10.1006/jmbi.2001.5296.

Abstract

B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations and has been associated with autoimmune disease. BAFF is known to interact with three receptors, BCMA, TACI and BAFF-R, that have distant similarities with other receptors of the TNF family. We have determined the crystal structure of the TNF-homologous domain of BAFF at 2.8 A resolution. The structure reveals significant differences when compared to other TNF family members, including an unusually long D-E loop that participates in the formation of a deep, concave and negatively charged region in the putative receptor binding site. The BAFF structure was further used to generate a homology model of APRIL, a closely related TNF family ligand that also binds to BCMA and TACI, but not BAFF-R. Analysis of the putative receptor binding sites of BAFF and APRIL suggests that differences in the D-E loop structure and electrostatic surface potentials may be important for determining binding specificities for BCMA, TACI and BAFF-R.

MeSH terms

  • Amino Acid Sequence
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • B-Lymphocytes / drug effects*
  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Evolution, Molecular
  • Humans
  • Hydrogen Bonding
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Membrane Proteins / pharmacology*
  • Models, Molecular
  • Molecular Sequence Data
  • Neuropeptides / chemistry
  • Neuropeptides / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Receptors, Tumor Necrosis Factor / chemistry
  • Receptors, Tumor Necrosis Factor / metabolism
  • Sequence Alignment
  • Solvents / metabolism
  • Static Electricity
  • Tumor Necrosis Factor-alpha / chemistry*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • ANP32B protein, human
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • Membrane Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Peptide Fragments
  • Receptors, Tumor Necrosis Factor
  • Solvents
  • TNFRSF13C protein, human
  • TNFSF13B protein, human
  • Tumor Necrosis Factor-alpha

Associated data

  • PDB/1KD7